Tissue-specific dysregulation of mitochondrial respiratory capacity and coupling control in colon-26 tumor-induced cachexia

In addition to skeletal muscle dysfunction, recent frameworks describe cancer cachexia as a systemic disease involving remodeling of non-muscle organs such as adipose and liver. Impairment of mitochondrial function is associated with multiple diseases. The tissue-specific control of mitochondrial fu...

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Bibliographic Details
Published inbioRxiv
Main Authors Khamoui, Andy V, Halle, Jessica L, Pena, Gabriel S, Paez, Hector G, Rossiter, Harry B, Visavadiya, Nishant P, Whitehurst, Michael A
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 11.12.2018
Subjects
Adipose tissue
Cachexia
Cancer
Cardiolipin
Colon
Electron transport
Energy balance
Liver
Liver cancer
Mitochondria
Mitochondrial uncoupling protein 2
Musculoskeletal system
Respiration
Skeletal muscle
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Summary:In addition to skeletal muscle dysfunction, recent frameworks describe cancer cachexia as a systemic disease involving remodeling of non-muscle organs such as adipose and liver. Impairment of mitochondrial function is associated with multiple diseases. The tissue-specific control of mitochondrial function in cancer cachexia is not well-defined. This study determined mitochondrial respiratory capacity and coupling control of skeletal muscle, white adipose tissue (WAT), and liver in colon-26 (C26) tumor-induced cachexia. Tissues were collected from PBS-injected weight-stable mice, C26 mice that were weight-stable, and C26 mice with moderate (10% weight loss) and severe cachexia (20% weight loss). WAT showed high non-phosphorylating LEAK respiration and reduced respiratory control ratio (RCR, index of OXPHOS coupling efficiency) during the induction of cachexia. Liver RCR decreased early due to cancer, and further declined with severe cachexia, where Ant2 but not Ucp2 expression was increased. Ant2 also related inversely with RCR in the liver (r=-0.547, p<0.01), suggesting a role for Ant2 in uncoupling of liver OXPHOS. Increased liver cardiolipin occurred during moderate cachexia and remained elevated in severe cachexia, suggesting this early event may also contribute to uncoupling. Impaired skeletal muscle mitochondrial respiration occurred predominantly in severe cachexia. These findings suggest that mitochondrial function is subject to tissue-specific control during cancer cachexia, whereby remodeling in WAT and liver arise early and could contribute to altered energy balance, followed by impaired skeletal muscle respiration. We highlight an underrecognized role of liver mitochondria in cancer cachexia, and suggest mitochondrial function of multiple tissues to be targets for therapeutic intervention.
DOI:10.1101/493056