Additionally, no meta-analysis has explored the optimal intake of CoQ10 for attenuating lipid profiles in adults.

Objective: This study conducted a meta-analysis to determine the effects of CoQ10 on lipid profiles and assess their dose-response relationships in adults. The novel single-stage restricted cubic spline regression model was applied to explore nonlinear dose-response relationships.

Results: Fifty randomized controlled trials with a total of participants were included in the qualitative synthesis. The pooled analysis revealed that CoQ10 supplementation significantly reduced total cholesterol TC MD Keywords: CoQ10 supplementation; dyslipidemia; lipid profiles; meta-analysis.

Published by Oxford University Press on behalf of the Endocrine Society. Appointments at Mayo Clinic Mayo Clinic offers appointments in Arizona, Florida and Minnesota and at Mayo Clinic Health System locations.

Request Appointment. Coenzyme Q Products and services. Coenzyme Q10 By Mayo Clinic Staff. Thank you for subscribing! Sorry something went wrong with your subscription Please, try again in a couple of minutes Retry.

Show references Coenzyme Q National Center for Complementary and Integrative Health. Accessed Oct. Pizzorono JE, et al. In: Textbook of Natural Medicine. Elsevier; Coenzyme Q10 PDQ -Health Professional Version. National Cancer Institute. IBM Micromedex. Dluda PV, et al. The impact of coenzyme Q10 on metabolic and cardiovascular disease profiles in diabetic patients: A systematic review and meta-analysis of randomized controlled trials.

Endocrinology, Diabetes and Metabolism. Goudarzi S, et al. Effect of vitamins and dietary supplements on cardiovascular health. Critical Paths in Cardiology. Natural Medicines.

Arenas-Jal M, et al. Coenzyme Q10 supplementation: Efficacy, safety, and formulation challenges. Comprehensive Reviews in Food Science and Food Safety. Mayo Clinic Press Check out these best-sellers and special offers on books and newsletters from Mayo Clinic Press.

Mayo Clinic on Incontinence - Mayo Clinic Press Mayo Clinic on Incontinence The Essential Diabetes Book - Mayo Clinic Press The Essential Diabetes Book Mayo Clinic on Hearing and Balance - Mayo Clinic Press Mayo Clinic on Hearing and Balance FREE Mayo Clinic Diet Assessment - Mayo Clinic Press FREE Mayo Clinic Diet Assessment Mayo Clinic Health Letter - FREE book - Mayo Clinic Press Mayo Clinic Health Letter - FREE book.

ART Home Coenzyme Q Show the heart some love! Give Today. Help us advance cardiovascular medicine. Find a doctor. Explore careers.

Sign up for free e-newsletters. About Mayo Clinic. About this Site. Contact Us. Health Information Policy. Media Requests. News Network. Price Transparency. Medical Professionals. Clinical Trials. Mayo Clinic Alumni Association.

J Cardiovasc Thorac Res. Singh RB, Neki NS, Kartikey K, Pella D, Kumar A, Niaz MA, et al. Effect of coenzyme Q10 on risk of atherosclerosis in patients with recent myocardial infarction. Mol Cell Biochem. Mohseni M, Vafa M, Zarrati M, Shidfar F, Hajimiresmail SJ, Rahimi FA. Beneficial effects of coenzyme Q10 supplementation on lipid profile and Intereukin-6 and intercellular adhesion Molecule-1 reduction, Preliminary Results of a Double-blind Trial in Acute Myocardial Infarction.

Int J Prev Med. Flowers N, Hartley L, Todkill D, Stranges S, Rees K. Co-enzyme Q10 supplementation for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev.

Nukui K, Yamagishi T, Miyawaki H, Kettawan A, Okamoto T, Belardinelli R, et al. Blood CoQ10 levels and safety profile after single-dose or chronic administration of PureSorb-Q animal and human studies. Pirro M, Mannarino MR, Bianconi V, Simental-Mendia LE, Bagaglia F, Mannarino E, et al.

The effects of a nutraceutical combination on plasma lipids and glucose: a systematic review and meta-analysis of randomized controlled trials.

Singh RB, Niaz MA. Serum concentration of lipoprotein a decreases on treatment with hydrosoluble coenzyme Q10 in patients with coronary artery disease: discovery of a new role. Int J Cardiol. McCall MR, Tang JY, Bielicki JK, Forte TM.

Inhibition of lecithin-cholesterol acyltransferase and modification of HDL apolipoproteins by aldehydes. Arterioscler Thromb Vasc Biol. Lee SK, Lee JO, Kim JH, Kim N, You GY, Moon JW, et al. Coenzyme Q10 increases the fatty acid oxidation through AMPK-mediated PPARalpha induction in 3T3-L1 preadipocytes.

Cell Signal. Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W. From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions.

Prog Lipid Res. Belardinelli R, Mucaj A, Lacalaprice F, Solenghi M, Seddaiu G, Principi F, et al. Coenzyme Q10 and exercise training in chronic heart failure.

Eur Heart J. Dai YL, Luk TH, Yiu KH, Wang M, Yip PM, Lee SW, et al. Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: a randomized controlled trial.

Mirhashemi SM, Najafi V, Raygan F, Asemi Z. The effects of coenzyme Q10 supplementation on cardiometabolic markers in overweight type 2 diabetic patients with stable myocardial infarction: a randomized, double-blind, placebo-controlled trial. ARYA Atheroscler. PubMed PubMed Central Google Scholar.

Pourmoghaddas M, Rabbani M, Shahabi J, Garakyaraghi M, Khanjani R, Hedayat P. Download references. The present study was supported by a grant from the Vice-chancellor for Research, SUMS, Shiraz, and Iran. The present study was founded by a grant from the Vice Chancellor for Research, Shiraz University of Medical Sciences, in Iran.

Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Health Policy Research Center, Institute of Health, Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.

School of Public Health, University of Saskatchewan, Saskatoon, SK, Canada. Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran. Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.

You can also search for this author in PubMed Google Scholar. ZA contributed in conception, design, statistical analysis and drafting of the manuscript. RT, VO, KL, PP, MA and FK contributed in data collection and manuscript drafting.

All authors approved the final version for submission. ZA supervised the study. Correspondence to Zatollah Asemi. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and permissions. Jorat, M. et al. The effects of coenzyme Q10 supplementation on lipid profiles among patients with coronary artery disease: a systematic review and meta-analysis of randomized controlled trials.

Lipids Health Dis 17 , Download citation. Received : 21 July Accepted : 26 September Published : 09 October Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Review Open access Published: 09 October The effects of coenzyme Q10 supplementation on lipid profiles among patients with coronary artery disease: a systematic review and meta-analysis of randomized controlled trials Mohammad Vahid Jorat 1 , Reza Tabrizi 2 , Naghmeh Mirhosseini 3 , Kamran B.

Abstract Background Chronic inflammation and increased oxidative stress significantly contribute in developing coronary artery disease CAD. Methods EMBASE, Scopus, PubMed, Cochrane Library, and Web of Science were searched for studies prior to May 20th, Results A total of eight trials participants in the intervention group and in placebo group were included in the current meta-analysis.

Conclusions This meta-analysis demonstrated the promising effects of CoQ10 supplementation on lowering lipid levels among patients with CAD, though it did not affect triglycerides, LDL-cholesterol and Lp a levels. Background Dyslipidemia is one of the major risk factor for establishing coronary artery disease CAD [ 1 ].

Methods PRISMA guideline the preferred reporting items for systematic reviews and meta-analyses was used to design and implement this meta-analysis. Search strategy Two independent authors RT and MA systematically searched online database including EMBASE, Scopus, PubMed, Cochrane Library, and Web of Science until 20th May Study selection Two investigators RT, MA independently screened all studies, retrieved from the online database and hand-search, using a two-stage process in order to determine eligible studies for current meta-analysis.

Data extraction and quality assessment The quality assessment and data extraction from each included trial were conducted by two independent investigators RT and MA , using Cochrane Collaboration risk of bias tool and standard Excel sheet-form , respectively.

Statistical analyses All statistical analyses were conducted using STATA version Results A total of studies were identified though our initial literatures search. Literature search and review flowchart for selection of studies. Full size image. Table 1 Characteristics of included studies Full size table.

Table 2 Estimation of the effects of CoQ10 supplementation on lipid profiles at baseline and the end of the treatment between intervention and placebo groups Full size table. Table 3 The assess of contribution each clinical trials in association between CoQ10 supplementation and lipid profiles based on sensitivity analysis Full size table.

Discussion The findings of current systematic review and meta-analysis showed that CoQ10 supplementation significantly improved lipid profiles by decreasing total cholesterol and increasing HDL-cholesterol levels, though did not affect triglycerides, LDL-cholesterol and Lp a levels in patients with CAD.

Conclusions CoQ10 supplementation significantly improved some of the parameters of lipid profile including total cholesterol and HDL-cholesterol levels in patients with CAD, though it might not affect the other parameters of lipid profiles.

Abbreviations HDL-C: high density lipoprotein-cholesterol LDL-C: Low density lipoprotein-cholesterol Lp a : Lipoprotein a RCTs: Randomized controlled trials TC: Total cholesterol TG: Triglycerides. References Liu HH, Li JJ. Article CAS Google Scholar Pisciotta L, Bertolini S, Pende A.

Article CAS Google Scholar Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, et al. Article CAS Google Scholar Knight-Lozano CA, Young CG, Burow DL, Hu ZY, Uyeminami D, Pinkerton KE, et al. Article CAS Google Scholar Madamanchi NR, Runge MS. Article CAS Google Scholar Singh U, Devaraj S, Jialal I.

Article Google Scholar Mortensen SA. Article CAS Google Scholar Shen Q, Pierce JD. Article Google Scholar Niklowitz P, Sonnenschein A, Janetzky B, Andler W, Menke T. Article CAS Google Scholar Sharifi N, Tabrizi R, Moosazadeh M, Mirhosseini N, Lankarani KB, Akbari M, et al.

Article CAS Google Scholar Suksomboon N, Poolsup N, Juanak N. Article CAS Google Scholar Sharifi MH, Eftekhari MH, Ostovan MA, Rezaianazadeh A. Article Google Scholar Singh RB, Neki NS, Kartikey K, Pella D, Kumar A, Niaz MA, et al. Article CAS Google Scholar Mohseni M, Vafa M, Zarrati M, Shidfar F, Hajimiresmail SJ, Rahimi FA.

Article Google Scholar Flowers N, Hartley L, Todkill D, Stranges S, Rees K. Article CAS Google Scholar Pirro M, Mannarino MR, Bianconi V, Simental-Mendia LE, Bagaglia F, Mannarino E, et al.

Article CAS Google Scholar Singh RB, Niaz MA. Article CAS Google Scholar McCall MR, Tang JY, Bielicki JK, Forte TM. Article CAS Google Scholar Lee SK, Lee JO, Kim JH, Kim N, You GY, Moon JW, et al.

Article CAS Google Scholar Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W. Article CAS Google Scholar Belardinelli R, Mucaj A, Lacalaprice F, Solenghi M, Seddaiu G, Principi F, et al. Article CAS Google Scholar Dai YL, Luk TH, Yiu KH, Wang M, Yip PM, Lee SW, et al.

Article CAS Google Scholar Mirhashemi SM, Najafi V, Raygan F, Asemi Z. PubMed PubMed Central Google Scholar Pourmoghaddas M, Rabbani M, Shahabi J, Garakyaraghi M, Khanjani R, Hedayat P.

PubMed PubMed Central Google Scholar Download references. Acknowledgements The present study was supported by a grant from the Vice-chancellor for Research, SUMS, Shiraz, and Iran. Funding The present study was founded by a grant from the Vice Chancellor for Research, Shiraz University of Medical Sciences, in Iran.

Availability of data and materials The primary data for this study is available from the authors on direct request. View author publications. Ethics declarations Ethics approval and consent to participate This study was considered exempt by the SUMS Institutional Review Board.

Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Rights and permissions Open Access This article is distributed under the terms of the Creative Commons Attribution 4.

About this article. Cite this article Jorat, M. Copy to clipboard. Sena et al. demonstrated that consumption of Q10 supplement reduces HbA 1 C in diabetic rats [ 17 ]. Also, Palyford et al. concluded that CoQ10 significantly decreases HbA1c. Similar with these findings, Hodgson et al.

showed that daily intake of mg Q10 in patients with diabetes results in decreasing of HbA1C and consequently long term improvement of glycemic control [ 19 ]. Conversely, the results of a number of published studies revealed no difference in glycemic control and requirement of insulin [ 25 - 27 ].

It has been shown that, Q10 levels are reduced in patients with diabetes, and might be responsible for β cell depressed function in type 2 diabetes [ 28 ]. Q10 impaired levels may induce insulin resistance via mitochondrial dysfunction [ 29 ].

There is an increased oxidative stress in patients with diabetes. Increased functional proteins glycosylation and glucose auto-oxidation are among other responsible mechanisms for ROS production and resulted in lipid peroxidation [ 30 ].

Q10 could enhance fatty acid oxidation through AMPK- mediated AMP activated protein kinase peroxisome proliferator-activated receptor α PRARα stimulation [ 31 ] which in turn increases lipoprotein lipase and APO-AV expression.

This may decreases TG an VLDL Levels [ 32 ]. Additionally it has been shown that PRARα agonist could increase LDL-C size which is more protective against vascular diseases [ 33 ].

PRARα can inhibit fatty acid and TG synthesis via reduction in SREBP1c and SREBP-2 maturation [ 34 ]. Antioxidant reserves have been decreased in patients with diabetes. Q10 supplementation may compensate this impaired antioxidant system and decrease oxidative stress in these patients.

Free fatty acids FFA and glucose overload in patients with diabetes tend to increase acetyle-COA production, and increase electron donors from TCA cycle and enhance membrane potential.

Increased membrane potential improve free radicals intermediates of Q10 half life that reduces O 2 to superoxide [ 35 ]. It has been shown that antioxidant treatment may reduce glucose levels [ 36 ] via β cell protection against ROS and glucose toxicity, and increased insulin secretion [ 35 ].

According to the results of our study HOMA-IR index and insulin levels did not change significantly, however HbA1c levels were significantly decreased. Due to short half-life of insulin, its level does not reflect its mean level in a prolonged period of time.

One of the main strength of this study was measurement of Q10 levels before and after intervention. There were some limitations in this study. The major limitation was that the inclusion criteria were wide. Proinsulin and C-peptide levels are better markers to show insulin production and β cell function; however these parameters were not measured.

Measurement of C-peptide levels would be beneficial, since insulin concentration in the portal vein ranges from two to ten times higher compared to the peripheral circulation.

Additionally fasting intact pro insulin could be used as a specific predictor of insulin resistance in type 2 diabetes [ 37 ]. Finally, it should keep in mind that uncontrolled and OTC consumption of any supplement could accompany by several unfavorable and hazardous effects [ 38 ].

In the case of Q10 supplementation for diabetics, lipid profile impairment needs special care. The results of the present study showed that 12 weeks supplementation with Q10 may improve glycemic control without favorable effects on lipid profiles of patients with diabetes.

Further larger studies are warranted to confirm these findings. Ghorbanihaghjo A, Kolahi S, Seifirad S, Rashtchizadeh N, Argani H, Hajialilo M, Khabazi A, Alizadeh S, Bahreini E: Effect of fish oil supplements on serum paraoxonase activity in female patients with rheumatoid arthritis: a double-blind randomized controlled trial.

Arch Iran Med , — CAS PubMed Google Scholar. QJM , — Article CAS PubMed Google Scholar. Wang XL, Rainwater DL, Mahaney MC, Stocker R: Cosupplementation with vitamin E and coenzyme Q10 reduces circulating markers of inflammation in baboons.

Am J Clin Nutr , — Article PubMed Google Scholar. Lim SC, Lekshminarayanan R, Goh SK, Ong YY, Subramaniam T, Sum CF, Ong CN, Lee BL: The effect of coenzyme Q10 on microcirculatory endothelial function of subjects with type 2 diabetes mellitus.

Atherosclerosis , — Littarru GP, Tiano L: Bioenergetic and antioxidant properties of coenzyme Q recent developments. Mol Biotechnol , 31— Kocharian A, Shabanian R, Rafiei-Khorgami M, Kiani A, Heidari-Bateni G: Coenzyme Q10 improves diastolic function in children with idiopathic dilated cardiomyopathy.

Cardiol Young , — Lenaz G, Fato R, Castelluccio C, Cavazzoni M, Estornell E, Huertas J, Pallotti F, Parenti Castelli G, Rauchova H: An updating of the biochemical function of coenzyme Q in mitochondria. Mol Aspects Med , s29—s Bradley R, Oberg EB, Calabrese C, Standish LJ: Algorithm for complementary and alternative medicine practice and research in type 2 diabetes.

J Altern Complement Med , — Calabrese V, Lodi R, Tonon C, D'Agata V, Sapienza M, Scapagnini G, Mangiameli A, Pennisi G, Stella A, Butterfield DA: Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia.

J Neurol Sci , — Emerit J, Edeas M, Bricaire F: Neurodegenerative diseases and oxidative stress. Biomed Pharmacother , 39— Bliznakov EG: Lipid-lowering drugs statins , cholesterol, and coenzyme Q The Baycol case—a modern Pandora's box. Biomed Pharmacother , 56— Lamson DW, Plaza SM: Mitochondrial factors in the pathogenesis of diabetes: a hypothesis for treatment.

Altern Med Rev , 7: 94— PubMed Google Scholar. Salles JE, Moisés VA, Almeida DR, Chacra AR, Moisés RS: Myocardial dysfunction in mitochondrial diabetes treated with Coenzyme Q Diabetes Res Clin Pract , — Suzuki S, Hinokio Y, Ohtomo M, Hirai M, Hirai A, Chiba M, Kasuga S, Satoh Y, Akai H, Toyota T: The effects of coenzyme Q10 treatment on maternally inherited diabetes mellitus and deafness, and mitochondrial DNA A to G mutation.

Diabetologia , — Lim S, Tan H, Goh S, Subramaniam T, Sum C, Tan I, Lee B, Ong C: Oxidative burden in prediabetic and diabetic individuals: evidence from plasma coenzyme Q Diabet Med , — Modi K, Santani D, Goyal R, Bhatt P: Effect of coenzyme Q10 on catalase activity and other antioxidant parameters in streptozotocin-induced diabetic rats.

Biol Trace Elem Res , 25— Sena CM, Nunes E, Gomes A, Santos MS, Proenca T, Martins MI, Seica RM: Supplementation of coenzyme Q10 and alpha-tocopherol lowers glycated hemoglobin level and lipid peroxidation in pancreas of diabetic rats. Nutr Res , — Kunitomo M, Yamaguchi Y, Kagota S, Otsubo K: Beneficial effect of coenzyme Q10 on increased oxidative and nitrative stress and inflammation and individual metabolic components developing in a rat model of metabolic syndrome.

J Pharmacol Sci , — Playford DA, Watts GF, Croft KD, Burke V: Combined effect of coenzyme Q10 and fenofibrate on forearm microcirculatory function in type 2 diabetes. Chew GT, Watts GF, Davis TM, Stuckey BG, Beilin LJ, Thompson PL, Burke V, Currie PJ: Hemodynamic effects of fenofibrate and coenzyme Q10 in type 2 diabetic subjects with left ventricular diastolic dysfunction.

Diabetes Care , — Article CAS PubMed PubMed Central Google Scholar. Hodgson JM, Watts GF, Playford DA, Burke V, Croft KD: Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes. Eur J Clin Nutr , — Witting PK, Pettersson K, Letters J, Stocker R: Anti-atherogenic effect of coenzyme Q10 in apolipoprotein E gene knockout mice.

Free Radic Biol Med , — Littarru GP, Tiano L: Clinical aspects of coenzyme Q an update. Nutrition , — Quiles JL, Ochoa JJ, Battino M, Gutierrez-Rios P, Nepomuceno EA, Frias ML, Huertas JR, Mataix J: Life-long supplementation with a low dosage of coenzyme Q10 in the rat: effects on antioxidant status and DNA damage.

Biofactors , 73— Eriksson JG, Forsen TJ, Mortensen SA, Rohde M: The effect of coenzyme Q10 administration on metabolic control in patients with type 2 diabetes mellitus. Biofactors , 9: — Henriksen JE, Andersen CB, Hother-Nielsen O, Vaag A, Mortensen SA, Beck-Nielsen H: Impact of ubiquinone coenzyme Q10 treatment on glycaemic control, insulin requirement and well-being in patients with Type 1 diabetes mellitus.

Coldiron AD Jr, Sanders RA, Watkins JB 3rd: Effects of combined quercetin and coenzyme Q 10 treatment on oxidative stress in normal and diabetic rats. J Biochem Mol Toxicol , — Taylor AA: Pathophysiology of hypertension and endothelial dysfunction in patients with diabetes mellitus.

Endocrinol Metab Clin North Am , — Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI: Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science , — Fagot-Campagna A, Pettitt DJ, Engelgau MM, Burrows NR, Geiss LS, Valdez R, Beckles GL, Saaddine J, Gregg EW, Williamson DF: Type 2 diabetes among North adolescents: An epidemiologic health perspective.

J Pediatr , — Lee SK, Lee JO, Kim JH, Kim N, You GY, Moon JW, Sha J, Kim SJ, Lee YW, Kang HJ, Park SH, Kim HS: Coenzyme Q10 increases the fatty acid oxidation through AMPK-mediated PPARalpha induction in 3 T3-L1 preadipocytes. Cell Signal , — Suckling KE, Jackson B: Animal models of human lipid metabolism.

Prog Lipid Res , 1— Ruotolo G, Ericsson CG, Tettamanti C, Karpe F, Grip L, Svane B, Nilsson J, de Faire U, Hamsten A: Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial BECAIT.

J Am Coll Cardiol , — Klopotek A, Hirche F, Eder K: PPAR gamma ligand troglitazone lowers cholesterol synthesis in HepG2 and Caco-2 cells via a reduced concentration of nuclear SREBP Exp Biol Med Maywood , — Schroeder MM, Belloto RJ Jr, Hudson RA, McInerney MF: Effects of antioxidants coenzyme Q10 and lipoic acid on interleukin-1 beta-mediated inhibition of glucose-stimulated insulin release from cultured mouse pancreatic islets.

Immunopharmacol Immunotoxicol , — Kajimoto Y, Kaneto H: Role of oxidative stress in pancreatic beta-cell dysfunction. Ann N Y Acad Sci , — Pfutzner A, Kunt T, Hohberg C, Mondok A, Pahler S, Konrad T, Lubben G, Forst T: Fasting intact proinsulin is a highly specific predictor of insulin resistance in type 2 diabetes.

Seifirad S, Ghaffari A, Amoli MM: The antioxidants dilemma: are they potentially immunosuppressants and carcinogens? Physiol , 5: Article PubMed PubMed Central Google Scholar. Download references. This work was supported by the Vice-Chancellor for Research, Iran University of Medical Sciences, Tehran, Iran.

Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular -Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.

Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.

Institute of Endocrinology and Metabolism, Firouzgar Hospital, Iran University of Medical Sciences, Tehran, Iran. Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. You can also search for this author in PubMed Google Scholar.

Correspondence to Shima Jazayeri. HZ participated in the statistical analysis, data interpretation and article writing. SE participated in the study design. SS participated in the statistical analysis and data interpretation.

NR participated in the study design. FS participated in the study design and data interpretation. IH participated in the data acquisition and interpretation. BG participated in the study design and statistical analysis. SJ participated in the study design, data interpretation, statistical analysis and article writing.

All authors read and approved the final manuscript. Reprints and permissions. Zahedi, H. et al. Effects of CoQ10 Supplementation on Lipid Profiles and Glycemic Control in Patients with Type 2 Diabetes: a randomized, double blind, placebo-controlled trial.

J Diabetes Metab Disord 13 , 81 Download citation. Received : 07 January Accepted : 13 July Published : 25 July Anyone you share the following link with will be able to read this content:.

Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Download PDF.

Abstract Background Low grade inflammation and oxidative stress are the key factors in the pathogenesis and development of diabetes and its complications. Methods Fifty patients with diabetes were randomly allocated into two groups to receive either mg CoQ10 or placebo daily for 12 weeks.

Refer to the supplementary data for the experimental protocol for 3T3L1 cells. Tissues and cells were lysed in cell lysis buffer Cell Signaling Technology, MA supplemented with protease inhibitors Sigma Aldrich, MO. Supernatants were collected, and protein concentrations were determined using the BCA protein Assay Kit Thermo Fisher Scientific, CO.

Target proteins were detected with the enhanced chemiluminescence ECL system and quantified using a densitometric image analyzer with Image-Pro Plus 4. The mixture was rotated in a 1. Total RNA was extracted using TRIzol Reagent Invitrogen, CA , followed by treatment with DNA-Free Applied Biosystems, CA to remove contaminating DNA and then subjected to reverse transcription using an Omniscript RT kit Applied Biosystems, CA with random primers Applied Biosystems, CA.

Quantitative real-time RT-PCR analysis was carried out using an ABI PRISM Sequence Detection System Applied Biosystems, CA with SYBR Green Takara Bio, Tokyo, Japan. Primer sequences are listed in Supplementary Table 1.

Blanks for spontaneous cAMP hydrolysis contained the corresponding buffer. Michaelis constant K m and maximum enzyme activity V max values were calculated from the X and Y intercepts.

Enrichment analysis was carried out using real-time PCR with specific primers. Kopelman, P. Obesity as a medical problem. Nature , — CAS PubMed Google Scholar. Kahn, S. Mechanisms linking obesity to insulin resistance and type 2 diabetes.

Article ADS CAS PubMed Google Scholar. Barrett-connor, E. Obesity, atherosclerosis, and coronary artery disease. Annals of Internal Medicine , — Article CAS PubMed Google Scholar. Kratz, M. The relationship between high-fat dairy consumption and obesity, cardiovascular, and metabolic disease.

European Journal of Nutrition 52 , 1—24 Wahba, I. Obesity and obesity-initiated metabolic syndrome: mechanistic links to chronic kidney disease. Clinical Journal of the American Society of Nephrology 2 , — Furukawa, S.

et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. The Journal of Clinical Investigation , — Article CAS PubMed PubMed Central Google Scholar. Keaney, J. Obesity and systemic oxidative stress. Arteriosclerosis, Thrombosis, and Vascular Biology 23 , — Özcan, U.

Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science , — Article ADS PubMed Google Scholar. Fu, S. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Article ADS CAS PubMed PubMed Central Google Scholar.

Mantena, S. Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol-and obesity-induced fatty liver diseases. Free Radical Biology and Medicine 44 , — Bournat, J. Mitochondrial dysfunction in obesity. Current Opinion in Endocrinology, Diabetes, and Obesity 17 , — Matsuoka, T.

Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells. Journal of Clinical Investigation 99 , — Rahmouni, K.

Obesity-associated hypertension: recent progress in deciphering the pathogenesis. Hypertension 64 , — Ohara, Y. Hypercholesterolemia increases endothelial superoxide anion production. Journal of Clinical Investigation 91 , — Berridge, M. The endoplasmic reticulum: a multifunctional signaling organelle.

Cell Calcium 32 , — Ozcan, L. Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity. Cell Metabolism 15 , — Park, S. Proceedings of the National Academy of Sciences of USA , — Article ADS CAS Google Scholar.

Cell Metabolism 18 , — Puigserver, P. Peroxisome proliferator-activated receptor-γ coactivator 1α PGC-1α : transcriptional coactivator and metabolic regulator. Endocrine Reviews 24 , 78—90 Liang, H.

PGC-1α: a key regulator of energy metabolism. Advances in Physiology Education 30 , — Article PubMed Google Scholar. Wright, D. Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1α expression.

Journal of Biological Chemistry , — Lehman, J. The transcriptional coactivator PGC-1α is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis. American Journal of Physiology-Heart and Circulatory Physiology , H—H Lagouge, M.

Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α.

Cell , — Lira, V. PGC-1α regulation by exercise training and its influences on muscle function and insulin sensitivity. American Journal of Physiology-Endocrinology and Metabolism , E—E CAS PubMed PubMed Central Google Scholar. Chalkiadaki, A. Sirtuins mediate mammalian metabolic responses to nutrient availability.

Nature Reviews. Endocrinology 8 , — Pfluger, P. Sirt1 protects against high-fat diet-induced metabolic damage. Colak, Y. SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease. Medical Science Monitor 17 , HY5—HY9 Article ADS PubMed PubMed Central Google Scholar.

Liang, F. SIRT1 and insulin resistance. Endocrinology 5 , — High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction.

Cell Metabolism 16 , — Costa Cdos, S. SIRT1 transcription is decreased in visceral adipose tissue of morbidly obese patients with severe hepatic steatosis. Obesity Surgery 20 , — Banks, A. SirT1 gain of function increases energy efficiency and prevents diabetes in mice.

Cell Metabolism 8 , — Lenaz, G. The function of coenzyme Q in mitochondria. Journal of Molecular Medicine 71 , S66—S70 CAS Google Scholar.

Quinone specificity of complex I. Biochimica et Biophysica Acta BBA -Bioenergetics , — Article CAS Google Scholar. Kalén, A. Age-related changes in the lipid compositions of rat and human tissues.

Lipids 24 , — Yang, Y. Coenzyme Q10 treatment of cardiovascular disorders of ageing including heart failure, hypertension and endothelial dysfunction.

Clinica Chimica Acta , 83—89 Safarinejad, M. Effects of the reduced form of coenzyme Q10 ubiquinol on semen parameters in men with idiopathic infertility: a double-blind, placebo controlled, randomized study. The Journal of Urology , — Toyama, K. Rosuvastatin combined with regular exercise preserves coenzyme Q10 levels associated with a significant increase in high-density lipoprotein cholesterol in patients with coronary artery disease.

Atherosclerosis , — Someya, S. Tomasetti, M. Coenzyme Q10 enrichment decreases oxidative DNA damage in human lymphocytes. Free Radical Biology and Medicine 27 , — Miyamae, T. Increased oxidative stress and coenzyme Q10 deficiency in juvenile fibromyalgia: amelioration of hypercholesterolemia and fatigue by ubiquinol supplementation.

Redox Report 18 , 12—19 Schmelzer, C. Micronutrient special issue: Coenzyme Q10 requirements for DNA damage prevention.

Tian, G. Ubiquinol supplementation activates mitochondria functions to decelerate senescence in senescence-accelerated mice. Bour, S. Coenzyme Q as an antiadipogenic factor. Lee, S. Coenzyme Q10 increases the fatty acid oxidation through AMPK-mediated PPARα induction in 3T3-L1 preadipocytes.

Cellular Signalling 24 , — Himms-Hagen, J. Thermogenesis in brown adipose tissue as an energy buffer: implications for obesity. New England Journal of Medicine , — Nguyen, P. Liver lipid metabolism. Journal of Animal Physiology and Animal Nutrition 92 , — Cantó, C.

Li, Y. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metabolism 13 , — Gerhart-Hines et al. Molecular Cell 44 , — Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases.

Bender, A. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacological Reviews 58 , — Angel, P.

The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochimica et Biophysica Acta BBA -Reviews on Cancer , — Kolch, W. Biochemical Journal , — Roux, P.

ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiology and Molecular Biology Reviews 68, Goetze, S. Atherosclerosis , 93— Cipolletta, E. Calmodulin-dependent kinase II mediates vascular smooth muscle cell proliferation and is potentiated by extracellular signal regulated kinase.

Endocrinology , — Grenier-Larouche et al. Omental adipocyte hypertrophy relates to coenzyme Q10 redox state and lipid peroxidation in obese women. Journal of Lipid Research 56 , — Iwatsuka, H.

General survey of diabetic features of yellow KK mice. Endocrinologia Japonica 17 , 23—35 Ventura-Clapier, R. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1α.

Cardiovascular Research 79 , — Gerhart-Hines, Z. The EMBO Journal 26 , — Carling, D. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis.

FEBS Letters , — Salminen, A. AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. Journal of Molecular Medicine 89 , — Steinberg, G.

AMPK in health and disease. Physiological Reviews 89 , — Ruderman, N. AMPK and SIRT1: a long-standing partnership?

Guarente, L. Sirtuins in aging and disease. In Cold Spring Harbor Symposia on Quantitative Biology Cold Spring Harbor Laboratory Press , pp.

Houtkooper, R. Sirtuins as regulators of metabolism and healthspan. Nature Reviews Molecular Cell Biology 13 , — Picard, F. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Arruda, A. Calcium homeostasis and organelle function in the pathogenesis of obesity and diabetes.

Cell Metabolism 22 , — Chang, Y. Coenzyme Q10 inhibits the release of glutamate in rat cerebrocortical nerve terminals by suppression of voltage-dependent calcium influx and mitogen-activated protein kinase signaling pathway.

Journal of Agricultural and Food Chemistry 60 , — Durán-Prado, M. Coenzyme Q10 protects human endothelial cells from β-amyloid uptake and oxidative stress-induced injury. PloS One 9 , e Download references. We thank the Kaneka Corporation of Japan for providing the mouse feed. We also thank Drs.

Kiyoshi Matsumoto and Takahiro Yoshizawa Research Center for Support to Advanced Science, Shinshu University for technical assistance and care of mice.

We thank Mr. Kiyokazu Kametani and Ms. Kayo Suzuki Research Center for Support to Advanced Science, Shinshu University for their skillful technical assistance.

Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, , Japan. Department of Advanced Medicine for Heath Promotion, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, , Japan.

Department of Biological Sciences for Intractable Neurological Diseases, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, , Japan. You can also search for this author in PubMed Google Scholar. conceived and designed experiments.

and J. performed the experiments. analyzed the data. and H. contributed reagents and materials. wrote the paper. Correspondence to Zhe Xu. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions. Xu, Z. Coenzyme Q10 Improves Lipid Metabolism and Ameliorates Obesity by Regulating CaMKII-Mediated PDE4 Inhibition. Sci Rep 7 , Download citation. Received : 04 May Accepted : 14 July Published : 15 August Anyone you share the following link with will be able to read this content:.

Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Naunyn-Schmiedeberg's Archives of Pharmacology Neuroscience and Behavioral Physiology By submitting a comment you agree to abide by our Terms and Community Guidelines.

If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. nature scientific reports articles article.

Download PDF. Other substrates of PARL did not show this correlation, indicating that PARL may counteract ferroptosis via STARD7. a , Correlation of high expression of PARL and STARD7 with the resistance of cancer cell lines to the GPX4 inhibitors ML, ML and RSL3. The whiskers represent the minimum and maximum value in the data, and outliers are indicated by a plus sign greater distance than 1.

b , Scheme illustrating FSP1-CoQ- and GPX4-dependent oxidative defence pathways as two independent mechanisms protecting against lipid peroxidation and ferroptosis image created with BioRender. Erastin treatment induced ferroptosis in a dose-dependent manner Extended Data Fig.

A combination of erastin and PUFA treatment boosted ferroptosis, which can be inhibited by the antioxidant ferrostatin-1 Fer1 or by supplementing cells with synthetic, soluble CoQ2, but not by the pan-caspase inhibitor QvD Fig. Cultivating cells in the presence of Fer1 or CoQ2 suppressed cell death under these conditions.

We also deleted PARL and STARD7 in the colon cancer cell line HCT Fig. Similar to HeLa cells, CoQ10 and CoQ9 levels were decreased in isolated monoclones lacking PARL or STARD7 Fig.

Thus, both PARL and STARD7 protect cells against ferroptosis upon inhibition of GPX4. Re-expression of STARD7 ensured the survival of STARD7-deficient cells under these conditions, substantiating the requirement of STARD7 for protection against ferroptosis Fig.

CoQ deficiency would impair ferroptosis defence in both the PM and the mitochondria via FSP1 and dihydroorotate dehydrogenase DHODH , respectively 19 , 20 , Rather, suppression of ferroptosis depends on STARD7 being present both in the IMS and the cytosol.

Cyto-STARD7 is dispensable for CoQ synthesis but required for suppression of ferroptosis even in cells that harbour STARD7 in the IMS and maintain CoQ synthesis.

To examine whether cyto-STARD7 limits the cellular resistance against ferroptosis, we overexpressed cyto-STARD7 in wild-type WT HeLa cells. We isolated three cell lines overexpressing cyto-STARD7 at different levels Extended Data Fig.

A kinetic analysis pointed towards a dose-dependent response, with ferroptosis occurring first in cells expressing the lowest levels of cyto-STARD7 Fig. No cell death was observed in WT and cyto-STARD7 overexpressing cells treated with DMSO.

It is conceivable that cyto-STARD7 expression increases CoQ synthesis, indirectly affecting ferroptotic resistance of the cells. However, we did not observe altered CoQ levels nor increased CoQ synthesis in 13 C 6 -glucose tracing experiments upon overexpression of cyto-STARD7 Extended Data Fig.

Together, these experiments demonstrate that the CoQ-dependent cellular resistance against ferroptosis depends on cytosolic STARD7, whose protein level limits ferroptosis induced by various stimuli. The identification of cyto-STARD7 as a ferroptosis suppressor acting independent of GPX4 suggests that cyto-STARD7 may promote the transport of CoQ from mitochondria to the PM, increasing the availability of CoQ and ferroptotic resistance.

We therefore examined whether the suppressive effect of cyto-STARD7 against ferroptosis depends on FSP1 in the PM. We induced ferroptosis in WT cells and cells expressing cyto-STARD7 and treated the cells concomitantly with the FSP1 inhibitor iFSP1.

FSP1 inhibition blunted the protective effect of cyto-STARD7 against ferroptosis induced with RSL3 Fig. To confirm that CoQ is required for the protective function of STARD7 against ferroptosis, we inhibited CoQ synthesis with 4-carboxybenzaldehyde 4-CBA , targeting the CoQ biosynthetic enzyme CoQ2 ref.

Together, these experiments demonstrate that cyto-STARD7 protects cells against ferroptosis via the FSP1-CoQ pathway in the PM. We then performed cellular fractionation experiments to directly monitor CoQ levels in the PM and in mitochondrial membranes Fig. A proteomic analysis of the cellular fractions obtained by differential centrifugation revealed the expected strong enrichment of mitochondrial proteins MitoCarta 3.

On the other hand, PM proteins were more broadly distributed among the different fractions but enriched in fraction 2 isolated by centrifugation at 12, g. However, fraction 3 isolated by centrifugation at 40, g contained the lowest number of mitochondrial proteins, further minimizing cross-contamination of the PM fraction with mitochondrial membranes that contain higher concentrations of CoQ than the PM We therefore used this PM fraction to assess how STARD7 affects the relative distribution of CoQ levels between the PM and mitochondrial membranes.

a , Scheme showing the fractionation protocol for HeLa cells to isolate mitochondria and PM fractions with differential centrifugations image created with BioRender. b , c , Heat maps showing the distribution of mitochondrial b and plasma membrane c proteins in different fractions of cells determined by MS.

CoQ distribution within the cell is indicated in per cent in each fraction. The loss of STARD7 was associated with decreased CoQ9 and CoQ10 levels in mitochondria and the PM Fig.

These results are consistent with the requirement of mito-STARD7 for CoQ synthesis and explain the increased ferroptotic vulnerability of cells lacking cyto-STARD7 by decreased CoQ levels in the PM.

We therefore conclude that mito-STARD7 is sufficient to maintain CoQ synthesis in mitochondria, whereas cyto-STARD7 preserves the CoQ pool in the PM, facilitating CoQ transport from mitochondria.

We substantiated these experiments determining CoQ levels in mitochondrial membranes fraction 1 and the PM fraction 3 of WT cells overexpressing cyto-STARD7 Fig. CoQ9 and CoQ10 levels were significantly increased in the PM fraction 3 of these cells.

On the other hand, mitochondrial CoQ10, but not CoQ9, was decreased in cells expressing cyto-STARD7 Fig. These data corroborate the critical role of cyto-STARD7 for cellular CoQ distribution and reveal that cyto-STARD7 limits CoQ accumulation in the PM.

To gain further insight into the role of STARD7 for CoQ transport to the PM, we examined a possible direct interaction of CoQ with STARD7 in vitro Fig.

STARD7 was purified after expression in Escherichia coli and incubated with liposomes containing CoQ variants differing in the length of their polyprenoid tail. After re-isolation of STARD7, we determined by mass spectrometry MS STARD7-associated CoQ variants that were extracted from liposomes Fig.

We detected CoQ4 in association with STARD7 but not in control samples, whereas the more hydrophobic variants CoQ9 and CoQ10 were not recovered. It is conceivable that their high hydrophobicity precludes their membrane extraction or their co-purification with STARD7 in vitro.

It should be noted that liposomes did not contain PC in these experiments, which is the known substrate of STARD7 ref. Increasing the PC concentration in liposomes indeed allowed the co-purification of an increasing amount of PC with STARD7, which was accompanied by decreased binding of CoQ4 to STARD7 Fig.

Thus, PC competes with CoQ4 for STARD7 binding. Consistently, mutating R within the lipid binding groove of STARD7, which was found to abolish PC binding 41 Fig. a , Scheme showing in vitro experiments, where liposomes containing different chain lengths of CoQ in the presence or absence of DOPC were incubated with STARD7 purified from E.

Top: after passing through a spin filter, lysate was analysed by MS. Purification of STARD7-his and its mutant variant RQ is shown. C-terminally hexahistidine-tagged mature form of STARD7 and its mutant variant were expressed in T7 express E. coli cells. After mechanical lysis, the lysate was subjected to Ni-NTA affinity purification followed by gel filtration.

b , CoQ extracted by STARD7 from liposomes containing either CoQ9 1 or CoQ10 2 or CoQ4 3 in the absence of DOPC was measured by MS. Background signals in the absence of protein were subtracted.

c , CoQ4 pMol and PC pMol extracted by STARD7. d , STARD7 and STARD7 RQ proteins purified from E. e , f , PC e and CoQ f extracted by STARD7 or STARD7 RQ from liposomes containing increasing concentration of DOPC.

Together, we conclude from these experiments that STARD7 can bind to CoQ4 in vitro, suggesting that it directly affects CoQ transport from mitochondria to the PM.

The cyto-STARD7-dependent cellular CoQ distribution points to a regulatory role of PARL, whose proteolytic activity determines the relative distribution of STARD7 between mitochondria and the cytosol.

While overexpression of cyto-STARD7 increases CoQ in the PM and protects against ferroptosis, it decreases CoQ levels in the mitochondria and thereby may affect mitochondrial functions.

We therefore examined how cyto-STARD7 overexpression affects the growth and respiratory competence of the cells. Expression of cyto-STARD7 did not affect cell growth in the presence of glucose Fig.

In contrast, cells harbouring increased levels of cyto-STARD7 grew significantly slower under respiring conditions on galactose-containing medium Fig. We observed significantly reduced basal and maximal respiration and ATP production, if cells overexpressing cyto-STARD7 were grown on galactose-containing medium Fig.

We did not observe any changes in the protein expression of OXPHOS subunits or CoQ biosynthetic machinery Extended Data Fig.

Thus, increased levels of cyto-STARD7 relative to mito-STARD7 confer ferroptotic resistance by increasing CoQ levels in the PM, but limit respiratory cell growth. These findings highlight the importance of regulating the relative accumulation of STARD7 in both compartments, the mitochondria and the cytosol.

Model illustrating the role of mito-STARD7 and cyto-STARD7 in CoQ biosynthesis and distribution, respectively. Source numerical data are available in source data image created with BioRender. We demonstrate that the lipid transfer protein STARD7 is required for both the synthesis of CoQ within mitochondria and for CoQ transport from mitochondria to the PM Fig.

PARL cleavage of STARD7 ensures the dual localization of STARD7 to the mitochondrial IMS and the cytosol, which allows coordination of CoQ synthesis and cellular CoQ distribution and balances mitochondrial respiration with the cellular defence against lipid peroxidation and ferroptosis.

PC transport across the IMS by mitochondrial STARD7 maintains CoQ levels independent of cytosolic STARD7, consistent with the critical role of mitochondria-localized STARD7 for cristae morphogenesis and respiration Whereas CoQ synthesis depends solely on mitochondrial STARD7, cytosolic STARD7 is required for CoQ transport from mitochondria to the PM and confers ferroptotic resistance to the cells.

Interestingly, STARD7 is the second START-domain protein besides COQ10 two orthologues exist in human involved in CoQ metabolism. Yeast Coq10 is dispensable for CoQ synthesis but cells lacking Coq10 exhibit an increased sensitivity to oxidative stress Coq10 binds CoQ and is thought to chaperone CoQ to sites of functions within mitochondria 42 , 47 , Similarly, we observed direct CoQ4 binding to STARD7 in vitro, indicating that STARD7 directly affects CoQ transport in vivo.

However, it remains to be determined whether STARD7 binding to CoQ results in a complete membrane extraction of CoQ, which appears unlikely considering the hydrophobicity of the polyprenoid tail of CoQ. Rather, a complex cellular machinery may drive the STARD7-dependent cellular distribution of CoQ, which mediates membrane remodelling and allows trafficking of newly synthesized CoQ, and perhaps additional membrane lipids, to other cellular membranes.

As previous complementation studies in yeast indicated that exogenously added CoQ can be transported via the endocytic pathway 49 , 50 , this may occur via vesicular transport. Moreover, it may involve contact sites between mitochondria and other cellular membranes, which often are characterized by lower PC concentrations and therefore represent membrane regions allowing CoQ binding by STARD7.

Although further mechanistic studies are needed to establish how STARD7 affects CoQ transport, our results identify STARD7 as a cytosolic component that is required for and also limits CoQ transport from mitochondria to the PM, offering new possibilities to further unravel this intriguing cellular pathway.

STARD7 is targeted to mitochondria where it is cleaved by PARL upon import into mitochondria and partitions between the IMS and the cytosol Our results demonstrate that this allows coordination of CoQ synthesis and intracellular transport, adjusting bioenergetic CoQ functions in mitochondria with functions of CoQ as antioxidants in the PM.

An imbalance in the cellular distribution of STARD7 has detrimental consequences for the cell: while low levels of STARD7 in the cytosol increase the susceptibility of the cells for ferroptosis, mitochondrial oxygen consumption and respiratory cell growth are impaired if levels of cytosolic STARD7 are increased relative to mitochondrial STARD7.

Our findings thus reveal the need to balance synthesis and distribution of CoQ by PARL-mediated processing of STARD7. It is conceivable that two conserved atypical kinases of the UbiB family in the IMS, which were demonstrated to modulate CoQ export from yeast mitochondria, participate in this regulation While our previous results identified PARL as a pro-apoptotic protein 32 , we demonstrate here that PARL and STARD7 maintain the CoQ- and FSP1-dependent antioxidant defence in the PM, limiting lipid peroxidation and ferroptosis.

These findings highlight the important role of mitochondrial CoQ synthesis and cellular CoQ distribution for the suppression of ferroptosis, which occurs independent of the anti-ferroptotic function of GPX4. PARL and STARD7 may therefore represent promising targets to induce ferroptosis in tumours resistant to GPX4 inhibitors.

On the other hand, ferroptosis has to be considered in genetic disorders caused by mutations in CoQ-synthesizing enzymes and in mitochondrial diseases with OXPHOS deficiencies As the loss of CoQ is emerging as a general consequence of OXPHOS defects 16 , 52 , an increased susceptibility to ferroptosis may be of broad importance for the pathophysiology of these diseases.

The research conducted here complies with all the relevant ethical regulations. All animal experiments were approved by Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen, Germany and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases CECAD mouse facility regulations.

HeLa CCL-2 cells were purchased from American Type Culture Collection ATCC. The human carcinoma colorectal HCT cell lines were bought from ATCC catalogue number HeL. For lentiviral transfection, HEKT cells were transfected with pLVX-puro containing either mito-STARD7 or cyto-STARD7 ref.

CoQ was extracted from cells using an extraction buffer methyl tertiary-butyl ether, MeOH and H 2 O v:v:v. A total of , cells per well were plated in a six-well plate, and CoQ was extracted the next day. For tracing experiments, cells were incubated with 13 C 6 -glucose for the indicated timepoints.

The pellets were used to determine protein concentrations using a bicinchoninic acid assay BCA. The UPLC was connected to a Tribrid Orbitrap HRMS, equipped with a heated ESI HESI source ID-X, Thermo Fisher Scientific. The resolution was set to ,, leading to approximately four scans per second.

All samples were analysed in a randomized run order. Targeted data analysis was performed using the quan module of the TraceFinder 4. For generating the graph of Fig. txt and v For all available compounds, table containing v This was done separately for all the genes of interest.

Oxygen consumption rate OCR was measured using Seahorse XF Analyzer. To normalize OCR data, protein concentration per well was determined using bicinchoninic acid assay. The data were analysed by Seahorse Wave Desktop software. We used an Incucyte Live-Cell Analysis system Sartorius to monitor cell death.

A total of 5, cells per well were plated in a well flat-bottom plate. To analyse the dead cell area, a mask was created by using the Incucyte base analysis software with basic analyser for both phase and green channels.

Area occupied by green objects was normalized to phase area per well to measure cell death. All compounds were bought from Sigma, including erastin E , RSL3 SML , ferrostatin-1 SML , CoQ2 C , QVD SML , FSP1 inhibitor SML , 4-CBA and arachidonic acid A , which was used as PUFA.

Mitochondrial and plasma membrane fractions were isolated from cells using differential centrifugation as described previously Whole cell WC sample was collected after homogenization.

Then, 8, g pellets were pooled together to collect mitochondrial fraction fraction 1. WC sample, 8, g fraction 1 , 12, g fraction 2 , 40, g fraction 3 and , g fraction 4 were used for proteomics analysis, and 8, g and 40, g pellets were used to extract CoQ. Gene encoding hexahistidine-tagged version of mature STARD7 76— was amplified from human complementary DNA and cloned into pET16b.

RQ variant was generated by site-directed mutagenesis PCR. The lysate was applied on HisTrap column Cytiva. All phospholipids were obtained from Avanti Polar Lipids. After cooling down on ice, the mixture was filtered through Amicon ultra 0.

A portion of flow through was subjected to SDS—PAGE to assess protein recovery. Fifty micrograms of protein was subjected to tryptic digestion. Samples were subjected to SP3-based digestion 1.

Formic acid and acetonitrile were added to a final concentration of 2. Instrumentation consisted out of an nLC LC system coupled via a nano-electrospray ionization source to a quadrupole-based mass spectrometer Exploris , Thermo Fisher Scientific.

A binary buffer system A: 0. The fixed first mass was set to The default charge state was set to 3. MS2 spectra were acquired as centroid spectra. The software DIA-NN v1. The spectral library was created using the reviewed only Uniport Mus musculus downloaded Protease was set to trypsin, and a maximum of one miscleavage was allowed.

N-term M excision was set as a variable modification and carbamidomethylation at cysteine residues was set as a fixed modification. Match between runs MBR was enabled. Statistical significance was assessed using a two-sided t -test on log 2 -transformed label-free quantitation LFQ intensities.

A permutation-based approach was used to control the FDR to 0. Data were analysed using Spectronaut4 Minimal peptide length was set to 7, and the maximum number of miscleavages was 2.

Dynamic mode to estimate mass tolerances for MS1 and MS2 was used. The maximum number of variable modifications was set to 5. Acetylation at the protein N-term and methionine residues oxidization were set as a variable modification.

Carbamidomethylation at cysteine residues was defined as a fixed modification. The iRT—rt regression type was set to local non-linear regression. Peptide grouping from precursors was done using the stripped peptide sequences.

Imputing was set off, and cross-run normalization was enabled. The peptide, peptide-spectrum match and protein group FDR were set to 0. The intensity-based absolute quantification iBAQ intensity was calculated and is reported.

For visualization, iBAQ intensities were scaled between 0 and 1 and visualized using hierarchical clustering Euclidean distance, complete method using the Instant Clue software. The MitoCarta 3. The set of PM proteins was extracted by using the Uniprot Gene Ontology cellular compartment information.

Supplementary Table 2 contains detailed information about the annotation process. Heat maps were created using the Instant Clue software using the complete method and correlation metrics to cluster rows. Columns were not clustered. Brains and hearts were extracted from mice and immediately frozen in the liquid nitrogen.

Tissues were then homogenized using mortar and pestle on dry ice and used for CoQ extraction. The protein pellets from CoQ extraction were further used for proteome analysis.

All the independent experiments or biological samples are represented in the graphs. Instant Clue software 3. No statistical method was used to pre-determine sample size.

No data were excluded from the analyses. The investigators for proteomics and metabolomics measurement were blinded to allocation during experiments and samples were randomized.

The investigators were not blinded for all other experiments, and samples were not randomized. The following commercial antibodies were used: SMAC MBL, JM dilution ,, STARD7 Proteintech AP dilution ,, FLAG WAKO dilution ,, SDHA Abcam Ab dilution ,, He dilution ,, CLPP Sigma HPA dilution ,, YME1L Proteintech AP dilution ,, MIC60 Nobus Biologicals dilution ,, VDAC2 Proteintech AP dilution , PARL antibody is defined previously 32 , dilution , Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

MS data have been deposited in ProteomeXchange with the primary accession code PXD Source data are provided with this paper. All other data supporting the findings of this study are available from the corresponding author on reasonable request.

Stefely, J. Biochemistry of mitochondrial coenzyme Q biosynthesis. Trends Biochem. Article CAS PubMed PubMed Central Google Scholar. Martinez-Reyes, I. et al. Mitochondrial ubiquinol oxidation is necessary for tumour growth.

Nature , — Jonassen, T. A dietary source of coenzyme Q is essential for growth of long-lived Caenorhabditis elegans clk-1 mutants. Natl Acad. USA 98 , — Luna-Sanchez, M. CoQ deficiency causes disruption of mitochondrial sulfide oxidation, a new pathomechanism associated with this syndrome.

EMBO Mol. Article CAS PubMed Google Scholar. Hernandez-Camacho, J. Coenzyme Q10 supplementation in aging and disease. Article PubMed PubMed Central Google Scholar. Wang, Y.

Understanding ubiquinone. Trends Cell Biol. Fernandez-Del-Rio, L. Coenzyme Q biosynthesis: an update on the origins of the benzenoid ring and discovery of new ring precursors.

Metabolites 11 , p Subramanian, K. Coenzyme Q biosynthetic proteins assemble in a substrate-dependent manner into domains at ER—mitochondria contacts. Cell Biol. Banerjee, R. The mitochondrial coenzyme Q junction and complex III: biochemistry and pathophysiology.

FEBS J. Hidalgo-Gutierrez, A. Metabolic targets of coenzyme Q10 in mitochondria. Antioxidants 10 , p Arias-Mayenco, I. Cell Metab. Pallotti, F. The roles of coenzyme Q in disease: direct and indirect involvement in cellular functions. Barcelos, I. CoQ10 and aging. Biology 8 , p28 Montini, G.

Early coenzyme Q10 supplementation in primary coenzyme Q10 deficiency. Med , — Doimo, M. Genetics of coenzyme q10 deficiency.

Kuhl, I. Transcriptomic and proteomic landscape of mitochondrial dysfunction reveals secondary coenzyme Q deficiency in mammals. eLife 6 , e Mourier, A. Mitofusin 2 is required to maintain mitochondrial coenzyme Q levels. Veling, M. Multi-omic mitoprotease profiling defines a role for Oct1p in coenzyme Q production.

Cell 68 , — e11 Bersuker, K. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Doll, S. FSP1 is a glutathione-independent ferroptosis suppressor. Kemmerer, Z. UbiB proteins regulate cellular CoQ distribution in Saccharomyces cerevisiae. Jiang, X. Ferroptosis: mechanisms, biology and role in disease.

Su, Y. Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs. Cancer Lett. Hirschhorn, T. The development of the concept of ferroptosis. Free Radic. Dixon, S. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell , — Mao, C. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer.

Stockwell, B. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Viswanathan, V. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.

Gan, B. Mitochondrial regulation of ferroptosis. Spinazzi, M.