| Literature DB >> 31639106 |
Divya Bhatia1, Kuei-Pin Chung2,3, Kiichi Nakahira2, Edwin Patino1, Michelle C Rice1, Lisa K Torres2, Thangamani Muthukumar1,4, Augustine Mk Choi2,4, Oleh M Akchurin4,5, Mary E Choi1,4.
Abstract
Mitophagy, by maintaining mitochondrial quality control, plays a key role in maintaining kidney function and is impaired in pathologic states. Macrophages are well known for their pathogenic role in kidney fibrosis. Here, we report that PINK1/Parkin-mediated mitophagy in macrophages is compromised in experimental and human kidney fibrosis. We demonstrate downregulation of mitophagy regulators mitofusin-2 (MFN2) and Parkin downstream of PINK1 in kidney fibrosis. Loss of either Pink1 or Prkn promoted renal extracellular matrix accumulation and frequency of profibrotic/M2 macrophages. Pink1-/- or Prkn-/- BM-derived macrophages (BMDMs) showed enhanced expression of rictor. Mitochondria from TGF-β1-treated Pink1-/- BMDMs exhibited increased superoxide levels, along with reduced respiration and ATP production. In addition, mitophagy in macrophages involves PINK1-mediated phosphorylation of downstream MFN2, MFN2-facilitated recruitment of Parkin to damaged mitochondria, and macrophage-specific deletion of Mfn2 aggravates kidney fibrosis. Moreover, mitophagy regulators were downregulated in human CKD kidney and TGF-β1-treated human renal macrophages, whereas Mdivi1 treatment suppressed mitophagy mediators and promoted fibrotic response. Taken together, our study is the first to our knowledge to demonstrate that macrophage mitophagy plays a protective role against kidney fibrosis via regulating the PINK1/MFN2/Parkin-mediated pathway.Entities:
Keywords: Fibrosis; Macrophages; Mitochondria; Nephrology
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Year: 2019 PMID： 31639106 PMCID： PMC6962025 DOI： 10.1172/jci.insight.132826
Source DB: PubMed Journal: JCI Insight ISSN： 2379-3708