Bhatia D.KUEI-PIN CHUNGNakahira K.Patino E.Rice M.C.Torres L.K.Muthukumar T.Choi A.M.K.Akchurin O.M.Choi M.E.2021-02-052021-02-0520192379-3708https://scholars.lib.ntu.edu.tw/handle/123456789/548777Mitophagy, 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. ? 2019, American Society for Clinical Investigation.[SDGs]SDG3adenosine triphosphate; alpha smooth muscle actin; cell protein; chemokine receptor CX3CR1; fibronectin; mannose receptor; mitofusin 2; parkin; phosphatase and tensin homolog induced kinase 1; protein serine threonine kinase; recombinant transforming growth factor beta1; rictor; superoxide; transforming growth factor beta1; unclassified drug; adenosine triphosphate; guanosine triphosphatase; MFN2 protein, human; Mfn2 protein, mouse; mitochondrial protein; parkin; protein kinase; PTEN-induced putative kinase; transcriptome; ubiquitin protein ligase; adult; animal cell; animal experiment; animal model; animal tissue; Article; bone marrow derived macrophage; controlled study; down regulation; extracellular matrix; female; gene deletion; human; human cell; kidney fibrosis; macrophage; male; middle aged; mitochondrial membrane potential; mitochondrial respiration; mitochondrion; mitophagy; mouse; nonhuman; nuclear reprogramming; protein expression; protein phosphorylation; protein synthesis; protein transport; renal protection; adolescent; animal; child; fibrosis; genetics; kidney; kidney disease; knockout mouse; macrophage; metabolism; mitophagy; pathology; phosphorylation; physiology; THP-1 cell line; Adenosine Triphosphate; Adolescent; Adult; Animals; Child; Female; Fibrosis; GTP Phosphohydrolases; Humans; Kidney; Kidney Diseases; Macrophages; Male; Mice; Mice, Knockout; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitophagy; Phosphorylation; Protein Kinases; THP-1 Cells; Transcriptome; Ubiquitin-Protein Ligasesjournal article10.1172/jci.insight.132826316391062-s2.0-85077735909