The multifaceted role of kidney tubule mitochondrial dysfunction in kidney disease development

Abstract

More than 800 million people suffer from kidney disease. Genetic studies and follow-up animal models and cell biological experiments indicate the key role of proximal tubule metabolism. Kidneys have one of the highest mitochondrial densities. Mitochondrial biogenesis, mitochondrial fusion and fission, and mitochondrial recycling, such as mitophagy are critical for proper mitochondrial function. Mitochondrial dysfunction can lead to an energetic crisis, orchestrate different types of cell death (apoptosis, necroptosis, pyroptosis, and ferroptosis), and influence cellular calcium levels and redox status. Collectively, mitochondrial defects in renal tubules contribute to epithelial atrophy, inflammation, or cell death, orchestrating kidney disease development.

Keywords: cell death; inflammation; kidney disease; mitochondria; mitophagy; renal tubule cell.

Fig.1. Compromised fatty acid metabolism leads to kidney function impairment.

Fatty acids are the main source of energy for kidney tubule epithelial cells and are oxidized by fatty acid oxidation and mitochondrial oxidative phosphorylation. Several transcription factors such as Estrogen Related Receptor Alpha (ESRRA), Peroxisome Proliferator Activated Receptor Alpha (PPARA) play an important role in regulating fatty acid oxidation in kidney tubules, in addition to peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a), which regulates mitochondrial biogenesis and metabolism. Lower expression of ESRRA, PGC1A, PPARA, and Carnitine Palmitoyltransferase 1A (CPT1A), was observed in acute and chronic kidney disease leading to impairment in fatty acid oxidation, subsequent reduction in ATP level, cellular lipid accumulation, contributing to functional impairment and dedifferentiation of tubule cells.

Fig.2. Increased mitochondrial reactive oxygen species (ROS) in kidney injury.

The citric acid cycle which takes place in the mitochondrial matrix generates cellular energy (ATP). The cycle consumes acetyl-CoA and water, reduces NAD⁺ to NADH, and releases carbon dioxide and water. Low NAD levels and NAD-dependent mitochondrial sirtuin activity in kidney disease are associated with impaired mitochondrial respiration, energy deficiency, and ROS accumulation in kidney tubule cells. The impaired Krebs cycle in damaged kidney tubule cells cause an energetic crisis. Cellular ATP in kidney tubule cells is critical for the re-absorptive capacity of proximal tubule cells. Increase cellular ROS can trigger cell death, specifically necroptosis, ferroptosis, and pyroptosis. Inflammatory cell death will cause the release of inflammatory cytokines.

Fig.3. Mitophagy plays key role in degrading impaired mitochondria

Mitophagy selectively eliminates damaged mitochondria. Mitochondrial injury can cause mitochondrial membrane depolarization and trigger mitophagy. Mitophagy receptors; PTEN Induced Kinase 1 (PINK1), PARKIN, FUN14 Domain Containing 1 (FUNDC1), BCL2 Interacting Protein 3 (BNIP3), NIX can initiate mitophagosome formation. Induction of mitophagy is followed by lysosome mitophagosome fusion, forming the mitolysosome. Impaired mitophagy can lead to the accumulation of defective mitochondria, inflammation, and worsening kidney injury.

Fig.4.. The key role of mitochondria in eliciting an inflammatory response.

The mitochondria can serve as a signaling platform to control inflammation. Mitochondrial DNA (mtDNA) is released from damaged mitochondria into the cytosol through BCL2-associated X protein (BAX)/ BCL2-antagonist/killer (BAK), mitochondrial permeability transition pore (mPTP), or by mitochondria herniation. Cytosolic nucleotides are recognized by several nucleotide sensing pathways such as Cyclic GMP–AMP synthase (cGAS) - Stimulator of interferon genes (STING)- Interferon Regulatory Factor 3 (IRF3)/ IRF7, Retinoic acid-inducible gene I (RIG-I)/ Melanoma differentiation-associated protein 5 (MDA5)-Mitochondrial antiviral signaling protein (MAVS). These pathways activate pro-inflammatory genes including interferon-stimulated genes. Genetic deletion or pharmacological inhibitor of cGAS/STING or RIG-I attenuated kidney disease development.

Fig.5.. Apoptosis

Proximal tubule apoptosis is a prominent feature of acute and chronic kidney disease. Intrinsic apoptosis is triggered by mitochondria damage. BCL2-associated X protein (BAX)/ BCL2-antagonist/killer (BAK) pores in the outer membrane of mitochondria will cause translocation of cytochrome c from the mitochondria to the cytosol to initiate the formation of the apoptosome consisting of caspase-9, Apaf1, and cytochrome-c. The apoptosome will activate executionary caspases such as caspase-3. Apoptosis will cause epithelial cell loss. Animal studies, analyzing BAX/BAK double KO, Caspase-9, and Caspase-3 KO mice or chemical caspase-inhibitors indicated the protective role of apoptosis from kidney disease development.

Fig.6.. The key role of mitochondria in kidney disease development.

The figure illustrates the overall biological changes in response to mitochondria damage in kidney tubules following toxic or ischemic injury. Mitochondrial injury in kidney tubule cells will lead to energy deficiency, increase reactive oxygen species (ROS) generation, the cytosolic release of mitochondrial DNA. Mitochondria biogenesis, change in shape, size, and turn-over play role in kidney tubule function. Severe injury will lead to cell death including apoptosis, necroptosis, pyroptosis, ferroptosis, and enhance inflammation and fibrosis by releasing pro-inflammatory cytokines, attracting immune cells, or activating fibroblasts.