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Autophagic clearance of mitochondria in the kidney copes with metabolic acidosis.

ABSTRACT: Metabolic acidosis, a common complication of CKD, causes mitochondrial stress by undefined mechanisms. Selective autophagy of impaired mitochondria, called mitophagy, contributes toward maintaining cellular homeostasis in various settings. We hypothesized that mitophagy is involved in proximal tubular cell adaptations to chronic metabolic acidosis. In transgenic mice expressing green fluorescent protein-tagged microtubule-associated protein 1 light chain 3 (GFP-LC3), NH4Cl loading increased the number of GFP puncta exclusively in the proximal tubule. In vitro, culture in acidic medium produced similar results in proximal tubular cell lines stably expressing GFP-LC3 and facilitated the degradation of SQSTM1/p62 in wild-type cells, indicating enhanced autophagic flux. Upon acid loading, proximal tubule-specific autophagy-deficient (Atg5-deficient) mice displayed significantly reduced ammonium production and severe metabolic acidosis compared with wild-type mice. In vitro and in vivo, acid loading caused Atg5-deficient proximal tubular cells to exhibit reduced mitochondrial respiratory chain activity, reduced mitochondrial membrane potential, and fragmented morphology with marked swelling in mitochondria. GFP-LC3-tagged autophagosomes colocalized with ubiquitinated mitochondria in proximal tubular cells cultured in acidic medium, suggesting that metabolic acidosis induces mitophagy. Furthermore, restoration of Atg5-intact nuclei in Atg5-deficient proximal tubular cells increased mitochondrial membrane potential and ammoniagenesis. In conclusion, metabolic acidosis induces autophagy in proximal tubular cells, which is indispensable for maintaining proper mitochondrial functions including ammoniagenesis, and thus for adapted urinary acid excretion. Our results provide a rationale for the beneficial effect of alkali supplementation in CKD, a condition in which autophagy may be reduced, and suggest a new therapeutic option for acidosis by modulating autophagy.

SUBMITTER: Namba T

PROVIDER: S-EPMC4178439 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Autophagic clearance of mitochondria in the kidney copes with metabolic acidosis.

Namba Tomoko T Takabatake Yoshitsugu Y Kimura Tomonori T Takahashi Atsushi A Yamamoto Takeshi T Matsuda Jun J Kitamura Harumi H Niimura Fumio F Matsusaka Taiji T Iwatani Hirotsugu H Matsui Isao I Kaimori Junya J Kioka Hidetaka H Isaka Yoshitaka Y Rakugi Hiromi H

Journal of the American Society of Nephrology : JASN 20140403 10

Metabolic acidosis, a common complication of CKD, causes mitochondrial stress by undefined mechanisms. Selective autophagy of impaired mitochondria, called mitophagy, contributes toward maintaining cellular homeostasis in various settings. We hypothesized that mitophagy is involved in proximal tubular cell adaptations to chronic metabolic acidosis. In transgenic mice expressing green fluorescent protein-tagged microtubule-associated protein 1 light chain 3 (GFP-LC3), NH4Cl loading increased the ...[more]

PMID: 24700866

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Project description:BackgroundCorrection of metabolic acidosis (MA) with nutritional therapy or bicarbonate administration is widely used in chronic kidney disease (CKD) patients. However, it is unknown whether these interventions reduce insulin resistance (IR) in diabetic patients with CKD. We sought to evaluate the effect of MA correction on endogenous insulin action in diabetic type 2 (DM2) CKD patients.MethodsA total of 145 CKD subjects (83 men e 62 women) with DM2 treated with oral antidiabetic drugs were included in the study and followed up to 1 year. All patients were randomly assigned 1:1 to either open-label (A) oral bicarbonate to achieve serum bicarbonate levels of 24-28 mmol/L (treatment group) or (B) no treatment (control group). The Homeostatic model assessment (HOMA) index was used to evaluate IR at study inception and conclusion. Parametric and non-parametric tests as well as linear regression were used.ResultsAt baseline no differences in demographic and clinical characteristics between the two groups was observed. Average dose of bicarbonate in the treatment group was 0.7 ± 0.2 mmol/kg. Treated patients showed a better metabolic control as confirmed by lower insulin levels (13.4 ± 5.2 vs 19.9 ± 6.3; for treated and control subjects respectively; p < 0.001), Homa-IR (5.9[5.0-7.0] vs 6.3[5.3-8.2]; p = 0.01) and need for oral antidiabetic drugs. The serum bicarbonate and HOMA-IR relationship was non-linear and the largest HOMA-IR reduction was noted for serum bicarbonate levels between 24 and 28 mmol/l. Adjustment for confounders, suggests that serum bicarbonate rather than treatment drives the effect on HOMA-IR.ConclusionsSerum bicarbonate is related to IR and the largest HOMA-IR reduction is noted for serum bicarbonate between 24 and 28 mmol/l. Treatment with bicarbonate influences IR. However, changes in serum bicarbonate explains the effect of treatment on HOMA index. Future efforts are required to validate these results in diabetic and non-diabetic CKD patients.Trial registrationThe trial was registered at www.clinicaltrial.gov (Use of Bicarbonate in Chronic Renal Insufficiency (UBI) study - NCT01640119 ).

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Autophagic clearance of mitochondria in the kidney copes with metabolic acidosis.

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Autophagic clearance of mitochondria in the kidney copes with metabolic acidosis.

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