The role of PGC-1alpha on mitochondrial function and apoptotic susceptibility in muscle

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Peter J Adhihetty, Giulia Uguccioni, Lotte Leick, Juan Hidalgo, Henriette Pilegaard, David A Hood

Mitochondria are critical for cellular bioenergetics, and they mediate apoptosis within cells. We used whole body peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) knockout (KO) animals to investigate its role on organelle function, apoptotic signaling, and cytochrome-c oxidase activity, an indicator of mitochondrial content, in muscle and other tissues (brain, liver, and pancreas). Lack of PGC-1alpha reduced mitochondrial content in all muscles (17-44%; P < 0.05) but had no effect in brain, liver, and pancreas. However, the tissue expression of proteins involved in mitochondrial DNA maintenance [transcription factor A (Tfam)], import (Tim23), and remodeling [mitofusin 2 (Mfn2) and dynamin-related protein 1 (Drp1)] did not parallel the decrease in mitochondrial content in PGC-1alpha KO animals. These proteins remained unchanged or were upregulated (P < 0.05) in the highly oxidative heart, indicating a change in mitochondrial composition. A change in muscle organelle composition was also evident from the alterations in subsarcolemmal and intermyofibrillar mitochondrial respiration, which was impaired in the absence of PGC-1alpha. However, endurance-trained KO animals did not exhibit reduced mitochondrial respiration. Mitochondrial reactive oxygen species (ROS) production was not affected by the lack of PGC-1alpha, but subsarcolemmal mitochondria from PGC-1alpha KO animals released a greater amount of cytochrome c than in WT animals following exogenous ROS treatment. Our results indicate that the lack of PGC-1alpha results in 1) a muscle type-specific suppression of mitochondrial content that depends on basal oxidative capacity, 2) an alteration in mitochondrial composition, 3) impaired mitochondrial respiratory function that can be improved by training, and 4) a greater basal protein release from subsarcolemmal mitochondria, indicating an enhanced mitochondrial apoptotic susceptibility.
Original languageEnglish
JournalAmerican Journal of Physiology: Cell Physiology
Volume297
Issue number1
Pages (from-to)C217-25
ISSN0363-6143
DOIs
Publication statusPublished - 2009

Bibliographical note

Keywords: Animals; Apoptosis; Apoptosis Regulatory Proteins; Cell Respiration; DNA, Mitochondrial; Electron Transport Complex IV; Hydrogen Peroxide; Kinetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria, Heart; Mitochondria, Muscle; Mitochondrial Membrane Transport Proteins; Mitochondrial Proteins; Muscle, Skeletal; Myocardium; Oxidative Stress; Physical Endurance; Physical Exertion; Reactive Oxygen Species; Trans-Activators

ID: 21360265