Conditional deletion of myeloid-specific mitofusin 2 but not mitofusin 1 promotes kidney fibrosis

Divya Bhatia, Allyson Capili, Kiichi Nakahira, Thangamani Muthukumar, Lisa K. Torres, Augustine M.K. Choi, Mary E. Choi

Research output: Contribution to journalArticlepeer-review

Abstract

Macrophages exert critical functions during kidney injury, inflammation, and tissue repair or fibrosis. Mitochondrial structural and functional aberrations due to an imbalance in mitochondrial fusion/fission processes are implicated in the pathogenesis of chronic kidney disease. Therefore, we investigated macrophage-specific functions of mitochondrial fusion proteins, mitofusin (MFN)1 and MFN2, in modulating macrophage mitochondrial dynamics, biogenesis, oxidative stress, polarization, and fibrotic response. MFN1 and MFN2 were found to be suppressed in mice after adenine diet-induced chronic kidney disease, in transforming growth factor-beta 1–treated bone marrow–derived macrophages, and in THP-1–derived human macrophages (a human leukemic cell line). However, abrogating Mfn2 but not Mfn1 in myeloid-lineage cells resulted in greater macrophage recruitment into the kidney during fibrosis and the macrophage-derived fibrotic response associated with collagen deposition culminating in worsening kidney function. Myeloid-specific Mfn1 /Mfn2 double knockout mice also showed increased adenine-induced fibrosis. Mfn2-deficient bone marrow–derived macrophages displayed enhanced polarization towards the profibrotic/M2 phenotype and impaired mitochondrial biogenesis. Macrophages in the kidney of Mfn2-deficient and double knockout but not Mfn1-deficient mice exhibited greater mitochondrial mass, size, oxidative stress and lower mitophagy under fibrotic conditions than the macrophages in the kidney of wild-type mice. Thus, downregulation of MFN2 but not MFN1 lead to macrophage polarization towards a profibrotic phenotype to promote kidney fibrosis through a mechanism involving suppression of macrophage mitophagy and dysfunctional mitochondrial dynamics.

Original languageEnglish (US)
Pages (from-to)963-986
Number of pages24
JournalKidney international
Volume101
Issue number5
DOIs
StatePublished - May 2022

Keywords

  • kidney fibrosis
  • macrophage
  • mitochondrial fusion
  • mitophagy
  • reactive oxygen species

ASJC Scopus subject areas

  • Nephrology

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