Mitochondrial Bioenergetic and Proteomic Phenotyping Reveals Organ-Specific Consequences of Chronic Kidney Disease in Mice

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.

The Association between Iron Deficiency and Renal Outcomes Is Modified by Sex and Anemia in Patients with Chronic Kidney Disease Stage 1–4

“…Altogether, we assumed that muscle wasting, malnutrition, and inflammation in the male subjects might contribute to markedly decreased serum iron bioavailability by upregulation of the iron regulatory hormone hepcidin [ 56 ]. As iron is essential for energy metabolism [ 3 ], it might induce unfavorable renal outcomes considering the high energy demand of the kidneys [ 16 , 17 ].…”

“…The clinical manifestations of iron deficiency are cognitive dysfunction [ 2 , 10 , 11 , 12 ], exacerbation of heart failure [ 9 , 13 , 14 ], impaired immune function [ 15 ], and decreased physical performance [ 1 , 15 ]. However, there is limited evidence exploring the effect of iron on renal function, even though the kidney is thought to possess high energy requirements [ 16 , 17 ]. Del Greco et al indicated that iron has a beneficial effect on kidney function in the general population [ 18 ].…”

Preventive Action of Beta-Carotene against the Indoxyl Sulfate-Induced Renal Dysfunction in Male Adult Zebrafish via Regulations of Mitochondrial Inflammatory and β-Carotene Oxygenase-2 Actions

“…The mitochondrial complex I functions is responsible for the oxidative phosphorylation-mediated ATP production and maintenance of a balanced mitochondrial respiratory chain [85]. In this condition, the mitochondrial Krebs cycle is involved in the oxidization of NADH for electron transfer for the reduction of ubiquinone to ubiquinol [86]. The alteration of the mitochondrial bioenergetics process is widely involved in the progression of CKD via oxidative stress and mitochondrial dysfunction [87].…”

Activation of the Aryl Hydrocarbon Receptor in Muscle Exacerbates Ischemic Pathology in Chronic Kidney Disease

“…References related to the methods used included previous studies. 25,[39][40][41][42][43][44][45][46][47]…”