Deletion of VDAC1 Hinders Recovery of Mitochondrial and Renal Functions After Acute Kidney Injury.

Grazyna Nowak,William J Craigen,Judit Megyesi

doi:10.3390/biom10040585

Grazyna Nowak, William J Craigen + Show 1 more

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https://doi.org/10.3390/biom10040585

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Journal: Biomolecules	Publication Date: Apr 10, 2020
Citations: 15	License type: CC BY 4.0

Affiliation: University of Arkansas for Medical Sciences

Abstract

Voltage-dependent anion channels (VDACs) constitute major transporters mediating bidirectional movement of solutes between cytoplasm and mitochondria. We aimed to determine if VDAC1 plays a role in recovery of mitochondrial and kidney functions after ischemia-induced acute kidney injury (AKI). Kidney function decreased after ischemia and recovered in wild-type (WT), but not in VDAC1-deficient mice. Mitochondrial maximum respiration, activities of respiratory complexes and FoF1-ATPase, and ATP content in renal cortex decreased after ischemia and recovered in WT mice. VDAC1 deletion reduced respiration and ATP content in non-injured kidneys. Further, VDAC1 deletion blocked return of activities of respiratory complexes and FoF1-ATPase, and recovery of respiration and ATP content after ischemia. Deletion of VDAC1 exacerbated ischemia-induced mitochondrial fission, but did not aggravate morphological damage to proximal tubules after ischemia. However, VDAC1 deficiency impaired recovery of kidney morphology and increased renal interstitial collagen accumulation. Thus, our data show a novel role for VDAC1 in regulating renal mitochondrial dynamics and recovery of mitochondrial function and ATP levels after AKI. We conclude that the presence of VDAC1 (1) stimulates capacity of renal mitochondria for respiration and ATP production, (2) reduces mitochondrial fission, (3) promotes recovery of mitochondrial function and dynamics, renal morphology, and kidney functions, and (4) increases survival after AKI.

Highlights

Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid decline in kidney function and failure to regulate fluid, electrolyte, and acid–base balance
Mitochondrial voltage-dependent anion channel-1 (VDAC1) levels did not change in WT sham animals, but decreased after ischemia with the lowest level found on day 3 post reperfusion
We conclude that VDAC1 is a major Voltage-dependent anion channels (VDACs) isoform that supports recovery of mitochondrial functions, dynamics, and remodeling after renal ischemia

Summary

Introduction

Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid decline in kidney function and failure to regulate fluid, electrolyte, and acid–base balance. A common mechanism for AKI is ischemia (inadequate O2 and nutrient delivery)-reperfusion injury, which involves mitochondrial dysfunction, oxidative stress, insufficient production of ATP, renal cell apoptosis and necrosis, and inflammation [1,2,3]. VDAC1 is the most abundant integral protein component of the outer mitochondrial membrane and, in physiological conditions, mediates the bidirectional transport of ions, nucleotides (e.g., NAD+/NADH, ADP/ATP), and solutes smaller than 5 kDa in size [6]. Apoptosis is associated with increased expression of VDAC1 in the outer mitochondrial membrane and oligomerization of VDAC1 monomers to form large channels that allow for release of mitochondrial pro-apoptotic proteins into the cytoplasm where they mediate additional apoptotic events [10,15,16,17]. Regulation of cell survival signals by VDAC1 occurs through its interactions with proteins of the Bcl-2 family, hexokinase, protein kinases, cytoskeletal proteins (tubulin, α-synuclein, plectin, and desmin), and mitochondrial lipids (cardiolipin and phoshatidylethanolamine) [16,17,18,19,20,21,22,23,24]

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