Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis

Bhatia, Divya; Chung, Kuei-Pin; Nakahira, Kiichi; Patiño, Edwin; Rice, Mary J.; Torres, Lisa; Muthukumar, Thangamani; Choi, Augustine M.K.; Akchurin, Oleh; Choi, Mary E.

doi:10.1172/jci.insight.132826

Cited by 119 publications

(102 citation statements)

References 52 publications

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“…Emerging evidence suggests that mitochondrial dysfunction is also a key contributor to the pathogenesis of CKD. Mitochondrial structural and functional impairments are increasingly recognized as critical mediators of many kidney diseases [12,20,56]. Here, we summarize recent advances in unraveling the functional significance of mitochondrial dysfunction in promoting inflammation and fibrotic responses in the pathogenesis of tubulointerstitial fibrosis (TIF) and various forms of CKD, including diabetic nephropathy (DN), IgA nephropathy (IgAN), membranous nephropathy (MN), and polycystic kidney disease (PKD).…”

Section: Mitochondrial Dysfunction In Chronic Kidney Diseasementioning

confidence: 99%

“…The GTPase activity of MFN1 is higher than that of MFN2, and OPA1 fails to execute the process of mitochondrial fusion in the absence of MFN1 [9,10]. MFN2, on the other hand, regulates mitophagy [11,12]. MFN2 also facilitates tethering and interaction between mitochondria and the endoplasmic reticulum (ER) at mitochondria-associated membranes (MAMs) and maintains efficient calcium (Ca 2+ ) uptake by mitochondria [13].…”

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confidence: 99%

“…MFN2 also facilitates tethering and interaction between mitochondria and the endoplasmic reticulum (ER) at mitochondria-associated membranes (MAMs) and maintains efficient calcium (Ca 2+ ) uptake by mitochondria [13]. Decreased expression of mitophagy regulators [12,14] or disruption of Ca 2+ signaling [15] in the kidney contributes to tubulointerstitial inflammation and kidney fibrosis.…”

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confidence: 99%

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Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

Bhatia¹,

Capili²,

Choi

2020

Kidney Res Clin Pract

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110

104

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Renal inflammation and tissue damage during acute kidney injury (AKI) and chronic kidney disease (CKD) have been linked to mitochondrial structural and functional alterations [1,2]. Mitochondria are a highly complex interconnected network of organelles that fulfill cellular energy needs. The kidney, an organ with high energy demands, is rich in mitochondria. Mitochondrial dysfunction arising from disturbances in the regulation of the mitochondrial electron transport chain (ETC), proton gradient, and membrane potential results in reduced adenosine triphosphate (ATP) and increased production of mitochondrial-derived reactive oxygen species (mROS), which promotes kidney injury and inflammation [3,4].

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Section: Mitochondrial Dysfunction In Chronic Kidney Diseasementioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

Bhatia¹,

Capili²,

Choi

2020

Kidney Res Clin Pract

Self Cite

110

104

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“…A recent study showed that phosphatase and tension homologue (PTEN)-induced kinase 1/ (PINK1)/mitofusion 2 (MFN2)/Parkin-mediated macrophage mitophagy is downregulated during kidney fibrosis, and loss of either Pink1 or Parkin promoted macrophage development toward profibrotic/M2 macrophages and subsequent renal fibrosis [50]. Additionally, autophagy induced by the histone deacetylase inhibitor, valproic acid, suppressed renal fibrosis in mice subjected to UUO [51].…”

Section: Autophagy In Renal Interstitial Fibrosis and Progressive Kidmentioning

confidence: 99%

Autophagy Function and Regulation in Kidney Disease

et al. 2020

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Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

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“…More recently, Bhatia et al report that PINK1-MFN2-PARK2 pathway of mitophagy in macrophages was compromised in experimental and human kidney fibrosis. Failure of this pathway of mitophagy resulted in accumulation of abnormal mitochondria, increased mtROS production, and increased RICTOR (RPTOR independent companion of MTOR complex 2) expression in macrophages, which in turn promoted the differentiation of macrophages toward profibrotic/M2 phenotype, leading to higher extracellular matrix production and progression of kidney fibrosis in UUO mice, suggesting that PINK1-MFN2-PARK2-mediated mitophagy in macrophages plays an anti-fibrotic role in kidneys [131]. Collectively, these findings suggest that mitophagy in renal tubular cells facilitates renal repair.…”

Section: Mitophagy In Kidney Repair and Renal Fibrosismentioning

confidence: 99%

Mitophagy in Acute Kidney Injury and Kidney Repair

Wang

Cai

Tang

et al. 2020

Cells

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Acute kidney injury (AKI) is a major kidney disease characterized by rapid decline of renal function. Besides its acute consequence of high mortality, AKI has recently been recognized as an independent risk factor for chronic kidney disease (CKD). Maladaptive or incomplete repair of renal tubules after severe or episodic AKI leads to renal fibrosis and, eventually, CKD. Recent studies highlight a key role of mitochondrial pathology in AKI development and abnormal kidney repair after AKI. As such, timely elimination of damaged mitochondria in renal tubular cells represents an important quality control mechanism for cell homeostasis and survival during kidney injury and repair. Mitophagy is a selective form of autophagy that selectively removes redundant or damaged mitochondria. Here, we summarize our recent understanding on the molecular mechanisms of mitophagy, discuss the role of mitophagy in AKI development and kidney repair after AKI, and present future research directions and therapeutic potential.

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Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis

Cited by 119 publications

References 52 publications

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

Autophagy Function and Regulation in Kidney Disease

Mitophagy in Acute Kidney Injury and Kidney Repair

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