Tubular Mitochondrial Dysfunction, Oxidative Stress, and Progression of Chronic Kidney Disease

Abstract

Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected conditions, and CKD is projected to become the fifth leading global cause of death by 2040. New therapeutic approaches are needed. Mitochondrial dysfunction and oxidative stress have emerged as drivers of kidney injury in acute and chronic settings, promoting the AKI-to-CKD transition. In this work, we review the role of mitochondrial dysfunction and oxidative stress in AKI and CKD progression and discuss novel therapeutic approaches. Specifically, evidence for mitochondrial dysfunction in diverse models of AKI (nephrotoxicity, cytokine storm, and ischemia-reperfusion injury) and CKD (diabetic kidney disease, glomerulopathies) is discussed; the clinical implications of novel information on the key role of mitochondria-related transcriptional regulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha, transcription factor EB (PGC-1α, TFEB), and carnitine palmitoyl-transferase 1A (CPT1A) in kidney disease are addressed; the current status of the clinical development of therapeutic approaches targeting mitochondria are updated; and barriers to the clinical development of mitochondria-targeted interventions are discussed, including the lack of clinical diagnostic tests that allow us to categorize the baseline renal mitochondrial dysfunction/mitochondrial oxidative stress and to monitor its response to therapeutic intervention. Finally, key milestones for further research are proposed.

Keywords: PGC-1α; acute kidney injury; chronic kidney disease; mitochondria; oxidative stress.

Figure 1

Mitochondrial function in healthy kidneys. Mitochondrial fatty acid β-oxidation (FAO) is the preferred pathway to generate ATP in kidney tubules. Fatty acids are converted in acyl-CoA in cytosol; they are conjugated with carnitine in the outer mitochondrial membrane (OMM) by carnitine palmitoyl-transferase 1A (CPT1A) to cross the inner mitochondrial membrane (IMM). In the mitochondrial matrix, acyl-carnitine is reconverted to acyl-CoA, and it enters the tricarboxylic acid (TCA) cycle. Reduced nicotinamide adenine dinucleotide (NADH₂) and reduced flavin adenine dinucleotide (FADH₂) generated by FAO and by the TCA cycle deposit their electrons into the electron transport chain (ETC). Electrons released by the ETC react with oxygen to form superoxide anion (O₂⁻), which is converted to hydrogen peroxide (H₂O₂) by superoxidase dismutase 2 (SOD2). H₂O₂ can be reduced to water by antioxidant enzymes such as catalase and glutathione peroxidases (GPXs).

Figure 2

Novel mitochondria-related therapeutic targets in kidney disease. The transcriptional activity of TFEB promotes the expression of genes involved in mitochondrial biogenesis such as PGC-1α and in antioxidant defenses. TFEB could be protective in AKI since it favors the degradation of damaged mitochondria and mitochondrial biogenesis. PGC-1α regulates the expression of TFEB, fatty acid β-oxidation (FAO), and electron transport chain (ETC) genes, mitochondrial transcription factors, and de novo NAD biosynthetic enzymes. Various reports have demonstrated that PGC-1α reduces renal inflammation and cell death and favors NAD synthesis and mitochondrial biogenesis. PGC-1α may also mediate the expression of carnitine palmitoyl-transferase 1A (CPT1A), which mediates the transport of fatty acids into the mitochondrial matrix. Overexpression of CPT1A in murine renal tubules protected from preclinical kidney disease by increasing ATP levels and reducing inflammation and fibrosis. ↑ increase; ↓ decrease.