☆ 4.7 Article

Differences in Mitochondrial Coupling Reveal a Novel Signature of Mitohormesis in Muscle of Healthy Individuals

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM (2016)

Journal

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM

Volume 101, Issue 12, Pages 4994-5003

Publisher

ENDOCRINE SOC

DOI: 10.1210/jc.2016-2742

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Funding

National Institutes of Health [R01 AG030226, R01 AG029914, U01 AG020478]
National Institutes of Health (Pennington/Louisiana Nutrition and Obesity Research Center) [P30 DK072476]
National Institutes of Health (Louisiana Clinical and Translational Science Center) [U54 GM104940]

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Abstract

Context: Reduced mitochondrial coupling (ATP/O-2 [P/O]) is associated with sedentariness and insulin resistance. Interpreting the physiological relevance of P/O measured in vitro is challenging. Objective: To evaluate muscle mitochondrial function and associated transcriptional profiles in nonobese healthy individuals distinguished by their in vivo P/O. Design: Individuals from an ancillary study of Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy phase 2 were assessed at baseline. Setting: The study was performed at Pennington Biomedical Research Center. Participants: Forty-seven (18 males, 26-50 y of age) sedentary, healthy nonobese individuals were divided into 2 groups based on their in vivo P/O. Intervention: None. Main Outcome(s): Body composition by dual-energy x-ray absorptiometry, in vivo mitochondrial function (P/O and maximal ATP synthetic capacity) by P-31-magnetic resonance spectroscopy and optical spectroscopy were measured. A muscle biopsy was performed to measure fiber type, transcriptional profiling (microarray), and protein expressions. Results: No differences in body composition, peak aerobic capacity, type I fiber content, or mitochondrial DNA copy number were observed between the 2 groups. Compared with the uncoupled group (lower P/O), the coupled group (higher P/O) had higher rates of maximal ATP synthetic capacity (maximal ATP synthetic capacity, P < .01). Transcriptomics analyses revealed higher expressions of genes involved in mitochondrial remodeling and the oxidative stress response in the coupled group. A trend for higher mitonuclear protein imbalance (P = .06) and an elevated mitochondrial unfolded protein response (heat shock protein 60 protein; P = .004) were also identified in the coupled group. Conclusions: Higher muscle mitochondrial coupling is accompanied by an overall elevation in mitochondrial function, a novel transcriptional signature of oxidative stress and mitochondrial remodeling and indications of an mitochondrial unfolded protein response.

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Reducing mitochondrial ribosomal gene expression does not alter metabolic health or lifespan in mice

Kim Reid, Eileen G. Daniels, Goutham Vasam, Rashmi Kamble, Georges E. Janssens, Iman M. Hu, Alexander E. Green, Riekelt H. Houtkooper, Keir J. Menzies

Summary: Maintaining mitochondrial function is crucial for improving healthspan and lifespan. Introducing mild stress through inhibiting mitochondrial translation leads to the unfolded protein response (UPRmt) and extends lifespan in animal models. However, reducing the expression of a key mitochondrial ribosomal protein (MRP), Mrpl54, did not significantly affect lifespan or metabolic health in genetically manipulated mice. This study suggests that, in otherwise healthy and unstressed mice, reducing Mrpl54 expression alone is not sufficient to improve healthspan.

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