Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis
Journal
JCI Insight
Journal Volume
4
Journal Issue
23
Date Issued
2019
Author(s)
Bhatia D.
Nakahira K.
Patino E.
Rice M.C.
Torres L.K.
Muthukumar T.
Choi A.M.K.
Akchurin O.M.
Choi M.E.
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. ? 2019, American Society for Clinical Investigation.
SDGs
Other Subjects
adenosine 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 Ligases
Type
journal article