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

Abstract

9In addition to skeletal muscle dysfunction, recent frameworks describe cancer cachexia as a systemic disease 3 0 involving remodeling of non-muscle organs such as adipose and liver. Impairment of mitochondrial function is 3 1 associated with multiple diseases. The tissue-specific control of mitochondrial function in cancer cachexia is 3 2 not well-defined. This study determined mitochondrial respiratory capacity and coupling control of skeletal 3 3 muscle, white adipose tissue (WAT), and liver in colon-26 (C26) tumor-induced cachexia. Tissues were 3 4 collected from PBS-injected weight-stable mice, C26 mice that were weight-stable, and C26 mice with 3 5 moderate (10% weight loss) and severe cachexia (20% weight loss). WAT showed high non-phosphorylating 3 6 LEAK respiration and reduced respiratory control ratio (RCR, index of OXPHOS coupling efficiency) during the 3 7 induction of cachexia. Liver RCR decreased early due to cancer, and further declined with severe cachexia, 3 8where Ant2 but not Ucp2 expression was increased. Ant2 also related inversely with RCR in the liver (r=-3 9 0.547, p<0.01), suggesting a role for Ant2 in uncoupling of liver OXPHOS. Increased liver cardiolipin occurred 4 0 during moderate cachexia and remained elevated in severe cachexia, suggesting this early event may also 4 1 contribute to uncoupling. Impaired skeletal muscle mitochondrial respiration occurred predominantly in severe 4 2 cachexia. These findings suggest that mitochondrial function is subject to tissue-specific control during cancer 4 3 cachexia, whereby remodeling in WAT and liver arise early and could contribute to altered energy balance, 4 4 followed by impaired skeletal muscle respiration. We highlight an underrecognized role of liver mitochondria in 4 5 cancer cachexia, and suggest mitochondrial function of multiple tissues to be targets for therapeutic 4 6 intervention. 4 7 4 disease, and cancer [13][14][15][16]. In particular, effects on mitochondrial respiration are important because oxidative 7 5 phosphorylation (OXPHOS), which couples the electron transfer system (ETS) to ADP phosphorylation, can 7 6 affect redox status, mitochondrial dynamics, quality control, and hence the overall health of the mitochondrial 7 7 pool [12]. In cancer cachexia, mitochondrial function has been most widely studied in skeletal muscle, with 7 8 several mechanisms proposed to link mitochondrial functions to muscle mass. Elevated oxidant emission 7 9 could lead to protein degradation and muscle atrophy [17, 18]. Further, restricted ATP provision from impaired 8 0 OXPHOS may cause energetic stress, downstream activation of protein degradation, and muscle dysfunction 8 1 [18, 19]. Indeed, recent reports found decreased complex I-linked OXPHOS capacity and coupling efficiency 8 2 in situ, and reduced coupling efficiency in vivo in skeletal muscle of rodents with cancer cachexia [20][21][22]. 8 3These defects were observed at or near timepoints in which marked cachexia already occurred, and are 8 4