Mitochondria play a key role in linking cell respiration to cell survival and are critical elements in many age- related degenerative pathologies: The mitochondrial theory of aging proposes that oxidative damage leads to irreversible mitochondrial dysfunction and tissue degeneration with age. New non-invasive methods developed in the last grant cycle have revealed significant mitochondrial uncoupling measured in vivo in aged mouse and human skeletal muscle that is at least partially reversible. This proposal builds on these findings to evaluate: 1)the mechanisms underlying in vivo mitochondrial dysfunction with age, and 2) the reversibility of each component of mitochondrial dysfunction. We employ state-of-the-art optical and magnetic resonance spectroscopic approaches to quantify in vivo deficits in mitochondrial ATP and Ozfluxes with age. The biochemical bases of these deficits are determined from in vitro tissue analysis of the same mouse muscles. We study wild-type mice over a range of ages to evaluate how accumulation of oxidative damage is related to mitochondrial defects and dysfunction in natural aging. Transgenic models with altered antioxidant activities and uncoupling protein (UCP3) expression are used to identify the underlying mechanisms of this dysfunction.
Aim 1 tests the roles of oxidative damage and uncoupling protein activity in the loss of mitochondrial coupling (reduced P/O) with age in wild-type and transgenic mice.
Aim 2 determines how respiratory chain defects impair respiratory function in vivo. We pair in vivo measurements of 62 flux with measures of oxidative damage to specific mitochondrial components at multiple ages in wild- type and transgenic mice.
Aim 3 tests the reversibility of the mitochondrial defects and dysfunction measured in Aims 1 and 2. Endurance exercise is used to increase mitochondrial proliferation and turnover, thereby replacing damaged mitochondria and improving function. The relevance of the proposed research to human health is two-fold. 1) The determination of the specific biochemical mechanisms leading to mitochondrial dysfunction will identify potential strategies to retard or reverse mitochondrial pathologies with age. 2) Our long-term goal is the development of non- invasive methods to diagnose mitochondrial dysfunction and follow the progress of interventions meant to reverse disability in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG028455-21S1
Application #
7460430
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Finkelstein, David B
Project Start
1988-10-01
Project End
2011-06-30
Budget Start
2007-07-15
Budget End
2008-06-30
Support Year
21
Fiscal Year
2007
Total Cost
$88,333
Indirect Cost
Name
University of Washington
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Marcinek, D J; Conley, K E (2014) In vivo metabolic spectroscopy identifies deficits in mitochondrial quality and capacity in aging skeletal muscle. Clin Pharmacol Ther 96:669-71
Siegel, Michael P; Kruse, Shane E; Percival, Justin M et al. (2013) Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell 12:763-71
Percival, Justin M; Siegel, Michael P; Knowels, Gary et al. (2013) Defects in mitochondrial localization and ATP synthesis in the mdx mouse model of Duchenne muscular dystrophy are not alleviated by PDE5 inhibition. Hum Mol Genet 22:153-67
Siegel, Michael P; Wilbur, Tim; Mathis, Mark et al. (2012) Impaired adaptability of in vivo mitochondrial energetics to acute oxidative insult in aged skeletal muscle. Mech Ageing Dev 133:620-8
Siegel, Michael P; Kruse, Shane E; Knowels, Gary et al. (2011) Reduced coupling of oxidative phosphorylation in vivo precedes electron transport chain defects due to mild oxidative stress in mice. PLoS One 6:e26963
Dai, Dao-Fu; Johnson, Simon C; Villarin, Jason J et al. (2011) Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res 108:837-46
Marcinek, David J; Kushmerick, Martin J; Conley, Kevin E (2010) Lactic acidosis in vivo: testing the link between lactate generation and H+ accumulation in ischemic mouse muscle. J Appl Physiol (1985) 108:1479-86
Dai, Dao-Fu; Chen, Tony; Wanagat, Jonathan et al. (2010) Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria. Aging Cell 9:536-44
Lee, Donghoon; Marcinek, David (2009) Noninvasive in vivo small animal MRI and MRS: basic experimental procedures. J Vis Exp :
Amara, Catherine E; Marcinek, David J; Shankland, Eric G et al. (2008) Mitochondrial function in vivo: spectroscopy provides window on cellular energetics. Methods 46:312-8

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