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

doi:10.1016/j.tcb.2022.03.012

Trends in Cell Biology

Volume 32, Issue 10, October 2022, Pages 841-853

https://doi.org/10.1016/j.tcb.2022.03.012 Get rights and content

Highlights

Kidney function genetic studies and follow-up omics functional analysis highlight the key role of kidney proximal tubules and metabolism in kidney disease development.
The kidneys have the second-highest mitochondrial density in the body to enable the active reabsorption of nutrients and electrolytes.
Altered redox balance, impaired cellular energetics, increased cell death, and inflammation are observed as consequences of mitochondrial dysfunction, causing kidney disease development.

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.

Section snippets

The key contribution of proximal tubule metabolism to kidney disease development

The kidney maintains electrolyte and fluid balance and secretes hormones. More than 800 million people suffer from kidney disease. Kidney dysfunction will cause toxin, fluid, and electrolyte build-up. Without treatment, kidney disease can progress to end-stage kidney failure requiring life-sustaining renal replacement therapy. New drug development for kidney disease is limited by our poor mechanistic understanding of disease pathogenesis. Kidney function genetic studies have highlighted

Energy balance

The primary function of the mitochondria is to generate ATP via a chain of biochemical reactions called the Krebs cycle [7]. Kidney tubules, especially proximal tubules transport kilograms of sodium chloride, other electrolytes, and nutrients daily. Kidney tubule cells preferentially oxidase fatty acids to generate energy (Figure 1). It has been known that kidney tubules can also burn ketones and lactate. While glucose utilization is almost undetectable in proximal renal tubules, it could be

Redox regulation and oxidative stress

Defective mitochondria fail to maintain the proton gradient across the inner mitochondrial membrane and are the main source of ROS in most cells (Figure 2). Under physiological conditions, 0.2–2% of the electrons in the electron transport chain do not follow the normal transfer but directly leak out of the electron transport chain and interact with oxygen to produce superoxide or hydrogen peroxide. Complexes I and III are considered to be the main sites for ROS production. In addition, NADPH

Mitochondria biogenesis

Mitochondrial numbers are a key determinant of mitochondrial function and the key mechanism to adapt to higher energy demand. Mitochondrial biogenesis is an important determinant of mitochondrial number. PGC1a is a master transcriptional regulator of mitochondrial biogenesis. Expression of PGC1a is lower in kidneys of patients with AKI and CKD [10]. Mice with genetic deletion of PCG1a appear healthy at baseline but show increased susceptibility to acute and chronic kidney injury [28]. At the

Mitochondria dynamics, shape, size, and turnover

Mitochondrial shape and size, which are controlled by fission and fusion, are other less well-understood determinants of function. Abnormalities in mitochondrial dynamics have been observed both in acute and chronic disease conditions [77]. Dynamin-related protein (DRP)1 is the master regulator of mitochondrial fission. Proximal-tubule-specific deletion of DRP1 or mdivi-1 treatment, a pharmacological inhibitor of DRP1, preserves mitochondrial structure, reduces oxidative stress, and protects

The role of mitochondria in controlling inflammation

Severe mitochondrial damage and defects in mitochondrial clearance can lead to a leakage of mtDNA into the cytosol. The exact mechanism of the mtDNA leakage is still not fully understood (Figure 4). BAK and BAX pores in the mitochondrial outer membrane can lead to inner mitochondrial membrane herniation and cytosolic release of mtDNA [6]. The presence of mtDNA in the cytosol is a sign of pathogenic infection and is recognized by the cytosolic nucleotide-sensing pathways. The nucleic acid

Apoptosis

The mitochondria play a key role in orchestrating a multitude of cell death mechanisms. Apoptosis is a noninflammatory cell death mechanism occurring without the rupture of the cell membrane. The release of cytochrome c from the mitochondria to the cytosol through BAX/BAK pores activates subsequent caspases such as caspase-9, followed by the activation of the execution caspases such as caspase-3 (Figure 5). Apoptosis has been observed in AKI and CKD and is likely a leading mechanism resulting

Concluding remarks

The kidney tubules have one of the highest mitochondrial densities to generate energy for the transport of large amounts of sodium and other solutes. Defects in mitochondrial biogenesis, dynamics, and mitophagy contribute to kidney disease development by the cells failing to meet the cellular energetic requirement. Mitochondrial damage has been widely recognized in AKI or CKD. Mitochondrial injury triggers multiple cell death mechanisms (apoptosis, necroptosis, pyroptosis, and ferroptosis)

Acknowledgments

This work was supported in the Susztak laboratory by the National Institute of Health NIH R01 DK087635, DK076077.

Declaration of Interests

The authors declare no competing interests.

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Trends in Cell Biology

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

Highlights

Section snippets

The key contribution of proximal tubule metabolism to kidney disease development

Energy balance

Redox regulation and oxidative stress

Mitochondria biogenesis

Mitochondria dynamics, shape, size, and turnover

The role of mitochondria in controlling inflammation

Apoptosis

Concluding remarks

Acknowledgments

Declaration of Interests

Trends Immunol.

Cell Metab.

EBioMedicine

Kidney Int.

Cell

Cell Death Dis.

Curr. Opin. Cell Biol.

Kidney Int.

Biomed. Pharmacother.

Redox Biol.

Cell Chem. Biol.

Lab. Investig.

Kidney Int.

Cell Death Dis.

Mitochondrion

Cell Metab.

Biochem. Biophys. Res. Commun.

Kidney Int.

Redox Biol.

Free Radic. Biol. Med.

Redox Biol.

J. Biol. Chem.

Cell

Cell Rep.

Immunity

Renal manifestations of genetic mitochondrial disease

Int. J. Nephrol. Renov. Dis.

Mitochondrial energetics in the kidney

Nat. Rev. Nephrol.

Renal metabolism and hypertension

Nat. Commun.

Regulated cell death in AKI

J. Am. Soc. Nephrol.

BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis

Science

Metabolic regulation of mitochondrial dynamics

J. Cell Biol.

Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development

Nat. Med.

Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis

J. Clin. Invest.

Impairment of PPARα and the fatty acid oxidation pathway aggravates renal fibrosis during aging

J. Am. Soc. Nephrol.

PPARα agonist fenofibrate enhances fatty acid β-oxidation and attenuates polycystic kidney and liver disease in mice

Am. J. Physiol. Ren. Physiol.

Fenofibrate-associated nephrotoxicity: a review of current evidence

Am. J. Health Syst. Pharm.

SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation

Nature

Regulation of MnSOD enzymatic activity by Sirt3 connects the mitochondrial acetylome signaling networks to aging and carcinogenesis

Antioxid. Redox Signal.

Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury

J. Clin. Invest.

Sirtuin 5 depletion impairs mitochondrial function in human proximal tubular epithelial cells

Sci. Rep.

Sirtuin 5 regulates proximal tubule fatty acid oxidation to protect against AKI

J. Am. Soc. Nephrol.

Mitochondrial biogenesis in kidney disease

J. Am. Soc. Nephrol.

De novo NAD(+) biosynthetic impairment in acute kidney injury in humans

Nat. Med.

Changes in NAD and lipid metabolism drive acidosis-induced acute kidney injury

J. Am. Soc. Nephrol.

Nicotinamide reduces renal interstitial fibrosis by suppressing tubular injury and inflammation

J. Cell. Mol. Med.

Nicotinamide mononucleotide, an NAD(+) precursor, rescues age-associated susceptibility to AKI in a sirtuin 1-dependent manner

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