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Review Open Access

Mitophagy and oxidative stress in chronic kidney disease (Review)

  • Authors:
    • Quwu Mushuo
    • Yihuai Tian
    • Jianchun Li
    • Yanqin Qiu
    • Hui Fan
    • Qiongdan Hu
    • Qiong Zhang
  • View Affiliations / Copyright

    Affiliations: Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China, Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
    Copyright: © Mushuo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 61
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    Published online on: December 4, 2025
       https://doi.org/10.3892/mmr.2025.13771
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Abstract

Chronic kidney disease (CKD) progression is driven by a harmful interplay between impaired mitophagy and sustained oxidative stress. Under normal conditions, mitophagy serves as a protective mechanism by removing damaged mitochondria and limiting the production of reactive oxygen species. However, in CKD, a self‑reinforcing cycle of mitochondrial dysfunction, defective mitophagy oxidative stress, and inflammation occurs, which promotes fibrosis. The present review examines the molecular mechanisms governing mitophagy, with a specific focus on the regulatory roles of core signaling pathways, namely the PTEN‑induced kinase l/Parkin, BCL2 interacting protein 3/Nip3‑like protein X and FUN14 domain‑containing protein l pathways, and how their disruption contributes to CKD. The mechanistic crosstalk between mitophagy and oxidative stress is highlighted as a central pathogenic axis in CKD progression. In addition, emerging therapeutic strategies that aim to restore mitophagy and enhance antioxidant capacity are discussed, suggesting new strategies for targeted CKD treatment.
View Figures

Figure 1

Schematic illustration of
mitochondrial dysfunction. When mitochondria are damaged by various
factors the MMP is reduced. The resulting mitochondrial dysfunction
decreases ATP production, increases ROS production and oxidative
stress. This triggers increased oxidative damage, renal epithelial
cell death, proinflammatory cytokines activation, inflammation and
fibrosis, resulting in CKD progression. MMP, mitochondrial membrane
potential; ATP, adenosine triphosphate; ROS, reactive oxygen
species; CKD, chronic kidney disease.

Figure 2

Schematic diagram of mitochondrial
dynamics. (A) Mitochondrial biogenesis. PGC-1α is a master
regulator of mitochondrial biogenesis, which controls mitochondrial
self-renewal and protects mtDNA. (B) Mitochondrial fission and
fusion. Fission is mainly mediated by Drp1, which severs the outer
and inner mitochondrial membranes, resulting in division of the
organelle into two daughter mitochondria. The primary mediators of
mitochondrial fusion are MFN1, MFN2 and OPA1. (C) Mitophagy.
Autophagosomes engulf the damaged mitochondria, which are targeted
by PINK, Parkin and Ub, and then delivered to lysosomes for
degradation. MFN2 promotes the translocation of Parkin to damaged
mitochondria when it is phosphorylated by PINK1. PGC-1α, peroxisome
proliferator-activated receptor-γ coactivator-1α; mtDNA,
mitochondrial DNA; Drp1, dynamin-related protein l; MFN1/2,
mitofusin 1/2; OPA1, optic atrophy protein l; PINK1, PTEN-induced
kinase 1; Ub, ubiquitin.

Figure 3

Molecular mechanisms of mitophagy.
(A) PINK1/Parkin pathway. Among the various mitophagy pathways, the
PINK1/Parkin pathway is the most well-characterized. Loss of MMP
causes PINK1 to accumulate on the OMM of the depolarized
mitochondria. and the recruitment of Parkin. PINK1 phosphorylates
Ub and Parkin, which converts Parkin into an active E3 Ub ligase.
PINK1 also phosphorylates MFN2, further promoting the recruitment
of Parkin to damaged mitochondria. Ub chains are tethered to
autophagy receptors, including p62, NBR1, NDP52, TAX1BP1 and OPTN,
that interact with LC3 on the autophagosome. NDP52 also binds to
the ULK1 complex, a process that is facilitated by the
TBK1-mediated phosphorylation of autophagy receptors. (B) BNIP3/NIX
and FUNDC1 pathways. The receptors BNIP3, NIX and FUNDC1 bind to
LC3, to induce mitophagy. Phosphorylation of the Tyr18 residue of
FUNDC1 by CK2α weakens the binding between LC3 and FUNDC1. By
contract, PGAM5 and ULK1 enhance the interaction of FUNDC1 with LC3
to promote mitophagy. (C) Nutrient deprivation-induced mitophagy.
Mitophagy induced by nutrient deprivation is primarily regulated by
mTOR, AMPK and SIRTs. Active mTORC1 suppresses mitophagy by
phosphorylating ULK1 while AMPK directly activates ULK1 through
phosphorylation. SIRT1, SIRT3 and SIRT5 have been shown to promote
mitophagy in animal models. PINK1, PTEN induced kinase l; MMP,
mitochondrial membrane potential; OMM, outer mitochondrial
membrane; Ub, ubiquitin; MFN2, mitofusin 2; p62, sequestosome 1;
NBR1, neighbor of BRCA1 gene l; NDP52, nuclear dot protein 52;
TAX1BP1, T-cell leukemia virus type I binding protein 1; OPTN,
optineurin; LC3, microtubule-associated protein 1 light chain 3;
ULK1, Unc-51 like autophagy activating kinase l; TBK1, TANK-binding
kinase 1; IMM, inner mitochondrial membrane; IMS, intermembrane
space; BNIP3, BCL2 interacting protein 3; NIX, Nip3-like protein X;
FUNDC1, FUN14 domain-containing protein l; Tyr18, tyrosine 18;
CK2α, casein kinase 2α; PGAM5, phosphoglycerate mutase family
member 5; mTOR, serine/threonine protein kinase mammalian target of
rapamycin; AMPK, AMP-activated protein kinase; SIRT, sirtuin
mTORC1, mTOR complex 1.

Figure 4

Diagram of mitochondria-related
oxidative stress. Oxidative stress contributes to disease by two
major mechanisms: ROS overproduction and the disruption of redox
homeostasis. Mitochondria are the primary source of intracellular
ROS. In the kidney, NOXs (NOX1, NOX2 and NOX4) and the
mitochondrial respiratory chain are the major contributors to the
production of ROS, which include O2•−,
•OH, H2O2 and
1O2. Diminished antioxidant capacity, due to
impaired activation of Nrf2, also contributes to oxidative stress.
NBR1 induces the phase separation of p62 and enhances the formation
of p62-containing liquid droplets. A positive feedback mechanism
exists, in which the p62-dependent degradation of Keap1 leads to
the accumulation of Nrf2, which activates the transcription of
antioxidant genes, including p62. The Keap1-Nrf2 pathway regulates
endogenous antioxidants, such as SOD and GPX. SOD rapidly converts
O2•− into H2O2, which
is then converted to water by GPX. However, if unquenched,
H2O2 can generate •OH radicals by reacting
with metal ions. ROS, reactive oxygen species; NOX, NADPH oxidase;
O2•−, superoxide anion radical;
•OH, hydroxyl radical; H2O2,
hydrogen peroxide; 1O2, singlet oxygen; Nrf2,
NF-E2-related factor 2; NBR1, neighbor of BRCA1 gene l; p62,
sequestosome 1; Keap1, Kelch-like ECH-associated protein 1; SOD,
superoxide dismutase; GPX, glutathione peroxidase; ATP, adenosine
triphosphate; MMP, mitochondrial membrane potential.
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Copy and paste a formatted citation
Spandidos Publications style
Mushuo Q, Tian Y, Li J, Qiu Y, Fan H, Hu Q and Zhang Q: Mitophagy and oxidative stress in chronic kidney disease (Review). Mol Med Rep 33: 61, 2026.
APA
Mushuo, Q., Tian, Y., Li, J., Qiu, Y., Fan, H., Hu, Q., & Zhang, Q. (2026). Mitophagy and oxidative stress in chronic kidney disease (Review). Molecular Medicine Reports, 33, 61. https://doi.org/10.3892/mmr.2025.13771
MLA
Mushuo, Q., Tian, Y., Li, J., Qiu, Y., Fan, H., Hu, Q., Zhang, Q."Mitophagy and oxidative stress in chronic kidney disease (Review)". Molecular Medicine Reports 33.2 (2026): 61.
Chicago
Mushuo, Q., Tian, Y., Li, J., Qiu, Y., Fan, H., Hu, Q., Zhang, Q."Mitophagy and oxidative stress in chronic kidney disease (Review)". Molecular Medicine Reports 33, no. 2 (2026): 61. https://doi.org/10.3892/mmr.2025.13771
Copy and paste a formatted citation
x
Spandidos Publications style
Mushuo Q, Tian Y, Li J, Qiu Y, Fan H, Hu Q and Zhang Q: Mitophagy and oxidative stress in chronic kidney disease (Review). Mol Med Rep 33: 61, 2026.
APA
Mushuo, Q., Tian, Y., Li, J., Qiu, Y., Fan, H., Hu, Q., & Zhang, Q. (2026). Mitophagy and oxidative stress in chronic kidney disease (Review). Molecular Medicine Reports, 33, 61. https://doi.org/10.3892/mmr.2025.13771
MLA
Mushuo, Q., Tian, Y., Li, J., Qiu, Y., Fan, H., Hu, Q., Zhang, Q."Mitophagy and oxidative stress in chronic kidney disease (Review)". Molecular Medicine Reports 33.2 (2026): 61.
Chicago
Mushuo, Q., Tian, Y., Li, J., Qiu, Y., Fan, H., Hu, Q., Zhang, Q."Mitophagy and oxidative stress in chronic kidney disease (Review)". Molecular Medicine Reports 33, no. 2 (2026): 61. https://doi.org/10.3892/mmr.2025.13771
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