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Kappler, L.* ; Hoene, M.* ; Hu, C.* ; von Toerne, C. ; Li, J.* ; Bleher, D.* ; Hoffmann, C.* ; Böhm, A. ; Kollipara, L.* ; Zischka, H. ; Königsrainer, A.* ; Häring, H.-U. ; Peter, A. ; Xu, G.* ; Sickmann, A.* ; Hauck, S.M. ; Weigert, C. ; Lehmann, R.

Linking bioenergetic function of mitochondria to tissue-specific molecular fingerprints.

Am. J. Physiol. Endocrinol. Metab. 317, E374-E387 (2019)
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Open Access Gold
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
Language english
Publication Year 2019
HGF-reported in Year 2019
ISSN (print) / ISBN 0193-1849
e-ISSN 1522-1555
Journal American Journal of Physiology - Endocrinology and Metabolism
Quellenangaben Volume: 317, Issue: 2, Pages: E374-E387 Article Number: , Supplement: ,
Publisher American Physiological Society
Publishing Place 9650 Rockville Pike, Bethesda, Md 20814 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)
CF Metabolomics & Proteomics (CF-MPC)
Institute of Molecular Toxicology and Pharmacology (TOX)
POF-Topic(s) 90000 - German Center for Diabetes Research
30203 - Molecular Targets and Therapies
Research field(s) Helmholtz Diabetes Center
Enabling and Novel Technologies
PSP Element(s) G-502400-001
G-505700-001
G-505200-003
A-630700-001
DOI 10.1152/ajpendo.00088.2019
WOS ID WOS:000481599900011
Scopus ID 85071068345
PubMed ID 31211616
Erfassungsdatum 2019-06-25
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