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Mitochondrial quality control in kidney injury and repair

Nature Reviews Nephrology volume 17, pages 299–318 (2021)Cite this article

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Abstract

Mitochondria are essential for the activity, function and viability of eukaryotic cells and mitochondrial dysfunction is involved in the pathogenesis of acute kidney injury (AKI) and chronic kidney disease, as well as in abnormal kidney repair after AKI. Multiple quality control mechanisms, including antioxidant defence, protein quality control, mitochondrial DNA repair, mitochondrial dynamics, mitophagy and mitochondrial biogenesis, have evolved to preserve mitochondrial homeostasis under physiological and pathological conditions. Loss of these mechanisms may induce mitochondrial damage and dysfunction, leading to cell death, tissue injury and, potentially, organ failure. Accumulating evidence suggests a role of disturbances in mitochondrial quality control in the pathogenesis of AKI, incomplete or maladaptive kidney repair and chronic kidney disease. Moreover, specific interventions that target mitochondrial quality control mechanisms to preserve and restore mitochondrial function have emerged as promising therapeutic strategies to prevent and treat kidney injury and accelerate kidney repair. However, clinical translation of these findings is challenging owing to potential adverse effects, unclear mechanisms of action and a lack of knowledge of the specific roles and regulation of mitochondrial quality control mechanisms in kidney resident and circulating cell types during injury and repair of the kidney.

Key points

  • Mitochondria are essential for cell viability but are highly susceptible to injury or damage.

  • Mitochondrial homeostasis depends on multiple quality control mechanisms, including antioxidant defence, protein quality control, mitochondrial DNA repair, mitochondrial dynamics, mitophagy and mitochondrial biogenesis.

  • Loss of mitochondrial quality control may induce mitochondrial damage and dysfunction, leading to cell death, tissue injury and possible organ failure.

  • Acute kidney injury (AKI) is characterized by sublethal and lethal damage to kidney tubules and incomplete or maladaptive kidney repair after AKI leads to kidney fibrosis and eventually chronic kidney disease (CKD).

  • Mitochondrial dysfunction has a critical role in the pathogenesis of AKI, abnormal kidney repair and CKD.

  • Modulation of mitochondrial quality control is a promising therapeutic approach to preventing and treating AKI and CKD and to accelerating kidney repair.

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Fig. 1: Mitochondrial functions and the effects of mitochondrial damage.
Fig. 2: Mitochondrial quality control.
Fig. 3: Mitochondrial fusion and fission.
Fig. 4: Molecular mechanisms of mitophagy.
Fig. 5: Regulation of mitochondrial biogenesis during AKI and repair.
Fig. 6: Targeting mitochondrial quality control mechanisms to protect against kidney injury and accelerate kidney repair in AKI and CKD.

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Authors and Affiliations

  1. Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, China

    Chengyuan Tang, Juan Cai & Zheng Dong

  2. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Xiao-Ming Yin

  3. Department of Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA

    Joel M. Weinberg

  4. Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Manjeri A. Venkatachalam

  5. Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA

    Zheng Dong

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  1. Chengyuan Tang
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  2. Juan Cai
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  4. Joel M. Weinberg
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  5. Manjeri A. Venkatachalam
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  6. Zheng Dong
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Contributions

C.T. and Z.D. researched the data for the article and wrote the manuscript. All authors contributed substantially to discussions of the content and revision of the manuscript before submission.

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Correspondence to Zheng Dong.

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Glossary

Electron transport chain

(ETC). A series of four protein complexes (complex I–IV) embedded in the inner mitochondrial membrane that transfer electrons from electron donors to electron acceptors via redox reactions. This process drives the transfer of protons across the inner mitochondrial membrane to produce ATP.

Hyperfused mitochondria

A network of elongated and highly connected mitochondria, which can result from increased fusion and/or reduced fission, and represent an adaptive response against stress.

Oxidative phosphorylation

(OXPHOS). A metabolic process in which the energy transferred by electrons from electron donors to electron acceptors through the electron transport chain via redox reactions drives the transport of protons across the inner mitochondrial membrane to generate a potential energy gradient. ATP synthase uses this energy to transform ADP into ATP in a phosphorylation reaction.

Fenton reaction

A catalytic process that converts hydrogen peroxide (H2O2) into highly reactive hydroxyl free radicals in the presence of ferrous iron (Fe(II)).

Mitochondrial cristae

Folds of the inner mitochondrial membrane that increase the surface area in which oxidative phosphorylation can occur and thus enhance the capacity of the mitochondrion to synthesize ATP.

Cristae junctions

Narrow, neck-like structures that connect the cristae membranes to the inner mitochondrial membrane. Cristae junctions act as a diffusion barrier that maintains the asymmetric protein composition between the inner mitochondrial membrane and cristae membranes and limits the diffusion of molecules, such as cytochrome c, from the intracristae space into the intermembrane space.

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Tang, C., Cai, J., Yin, XM. et al. Mitochondrial quality control in kidney injury and repair. Nat Rev Nephrol 17, 299–318 (2021). https://doi.org/10.1038/s41581-020-00369-0

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