Abstract
Chronic kidney disease (CKD) results in reduced kidney function, uremia, and accumulation of uremic metabolites. Mitochondrial alterations have been suggested to play a role in the disease pathology within various tissues. The purpose of this study was to perform a comprehensive bioenergetic and proteomic phenotyping of mitochondria from skeletal muscle (SkM), cardiac muscle (CM), and renal tissue from mice with CKD. The 5-month-old C57BL/6J male mice were fed a casein control or adenine-supplemented diet for 6 months. CKD was confirmed by blood urea nitrogen. A mitochondrial diagnostic workflow was employed to examine respiratory function, membrane and redox potential, reactive oxygen species production, and maximal activities of matrix dehydrogenases and electron transport system (ETS) protein complexes. Additionally, tandem-mass-tag-assisted proteomic analyses were performed to uncover possible differences in mitochondrial protein abundance. CKD negatively impacted mitochondrial energy transduction (all p < 0.05) in SkM, CM, and renal mitochondria, when assessed at physiologically relevant cellular energy demands (ΔGATP) and revealed the tissue-specific impact of CKD on mitochondrial health. Proteomic analyses indicated significant abundance changes in CM and renal mitochondria (115 and 164 proteins, p < 0.05), but no differences in SkM. Taken together, these findings reveal the tissue-specific impact of chronic renal insufficiency on mitochondrial health.
Highlights
Chronic kidney disease (CKD) stems from a progressive decline in renal function that results in elevated uremia and the accumulation of uremic metabolites which have deleterious effects on metabolism [1,2,3]
Skeletal muscle, cardiac muscle, and renal tissue were targeted for bioenergetic assessments in this study due to their high metabolic demand for energy (ATP)
Required for cellular tasks such as contraction or production of ion gradients utilized for reabsorption or excretion of metabolites
Summary
Chronic kidney disease (CKD) stems from a progressive decline in renal function that results in elevated uremia and the accumulation of uremic metabolites which have deleterious effects on metabolism [1,2,3]. Many studies have described impaired metabolism and mitochondrial dysfunction in multiple tissue types around the body including skeletal muscle, cardiac muscle, and renal tissue [8,9,13,14,15,16,17,18,19,20,21] These altered metabolic functions have been associated with muscle wasting, reduced muscular strength and exercise capacity, impaired growth and insulin signaling, left ventricular hypertrophy, increased cardiovascular events, metabolic acidosis, abnormal mitochondrial morphology, and increased oxidative stress [9,10,16,20,21]
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