Halle 2019 Am J Physiol Regul Integr Comp Physiol
|Halle JL, Pena GS, Paez HG, Castro AJ, Rossiter HB, Visavadiya NP, Whitehurst MA, Khamoui AV (2019) Tissue-specific dysregulation of mitochondrial respiratory capacity and coupling control in colon-26 tumor-induced cachexia. Am J Physiol Regul Integr Comp Physiol [Epub ahead of print].|
Abstract: In addition to skeletal muscle dysfunction, cancer cachexia is a systemic disease involving remodeling of non-muscle organs such as adipose and liver. Impairment of mitochondrial function is associated with multiple chronic 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 weight-stable mice, and C26 mice with moderate (10% weight loss) and severe cachexia (20% weight loss). The respiratory control ratio (RCR, an index of OXPHOS coupling efficiency) was low in WAT during the induction of cachexia, due to high non-phosphorylating LEAK respiration. Liver RCR was low in C26 weight-stable and moderately cachexic mice due to reduced OXPHOS. Liver RCR was further reduced with severe cachexia, where Ant2 but not Ucp2 expression was increased. Ant2 was inversely correlated with RCR in the liver (r=-0.547, p<0.01). Liver cardiolipin increased in moderate and severe cachexia, suggesting this early event may also contribute to mitochondrial uncoupling. Impaired skeletal muscle mitochondrial respiration occurred predominantly in severe cachexia, at complex I. These findings suggest that mitochondrial function is subject to tissue-specific control during cancer cachexia, whereby remodeling in WAT and liver arise early and may contribute to altered energy balance, followed by impaired skeletal muscle respiration. We highlight an under-recognized role of liver and WAT mitochondrial function in cancer cachexia, and suggest mitochondrial function of multiple tissues to be therapeutic targets.
Labels: MiParea: Respiration Pathology: Cancer
Organism: Mouse Tissue;cell: Skeletal muscle, Liver, Fat Preparation: Intact cells, Permeabilized tissue
Coupling state: LEAK, OXPHOS, ET Pathway: F, N, S, NS, ROX HRR: Oxygraph-2k