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Linking bioenergetic function of mitochondria to tissue-specific molecular fingerprints.
Am. J. Physiol. Endocrinol. Metab. 317, E374-E387 (2019)
Mitochondria are dynamic organelles with diverse functions in tissues such as liver and skeletal muscle. To unravel the mitochondrial contribution to tissue-specific physiology, we performed a systematic comparison of the mitochondrial proteome and lipidome of mice and assessed the consequences hereof for respiration. Liver and skeletal muscle mitochondrial protein composition was studied by data-independent ultra-high-performance (UHP)LC-MS/MS-proteomics, and lipid profiles were compared by UIIPLC-MS/MS lipidomics. Mitochondrial function was investigated by high-resolution respirometry in samples from mice and humans. Enzymes of pyruvate oxidation as well as several subunits of complex I, III, and ATP synthase were more abundant in muscle mitochondria. Muscle mitochondria were enriched in cardiolipins associated with higher oxidative phosphorylation capacity and flexibility, in particular CL(18:2)(4) and 22:6-containing cardiolipins. In contrast, protein equipment of liver mitochondria indicated a shuttling of complex I substrates toward gluconeogenesis and ketogenesis and a higher preference for electron transfer via the flavoprotein quinone oxidoreductase pathway. Concordantly, muscle and liver mitochondria showed distinct respiratory substrate preferences. Muscle respired significantly more on the complex I substrates pyruvate and glutamate, whereas in liver maximal respiration was supported by complex II substrate succinate. This was a consistent finding in mouse liver and skeletal muscle mitochondria and human samples. Muscle mitochondria are tailored to produce ATP with a high capacity for complex I-linked substrates. Liver mitochondria are more connected to biosynthetic pathways, preferring fatty acids and succinate for oxidation. The physiologic diversity of mitochondria may help to understand tissue-specific disease pathologies and to develop therapies targeting mitochondrial function.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Cardiolipins ; Liver ; Mitochondria ; Multi-omics ; Muscle; Skeletal-muscle; Respiratory-chain; Oxidative-phosphorylation; Supercomplex Formation; Linoleic-acid; Cardiolipin; Liver; Phospholipids; Gluconeogenesis; Dysfunction
ISSN (print) / ISBN
0193-1849
e-ISSN
1522-1555
Quellenangaben
Volume: 317,
Issue: 2,
Pages: E374-E387
Publisher
American Physiological Society
Publishing Place
9650 Rockville Pike, Bethesda, Md 20814 Usa
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Peer reviewed