Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis.

Overview

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.

Summary

Our present studies provide a mechanistic understanding of the role of PINK1/MFN2/Parkin-mediated macrophage mitophagy and its role in the context of kidney fibrosis. Our findings indicate that the mitophagy regulators are downregulated in experimental animal models of kidney fibrosis, in renal macrophages from fibrotic kidney, in TGF-β1–treated primary mouse BMDMs and human renal macrophages, and in the human CKD kidney. The deficiency of mitophagy regulators contributes to mitochondrial dysfunction, impaired mitophagy, and elevated levels of mROS and rictor expression, both of which promote macrophage reprogramming toward profibrotic/M2 phenotype (Figure 9). Therefore, it may be prudent to investigate the potential of therapeutically targeting the negative regulators of mitophagy to modulate the macrophage-derived progression of kidney fibrosis and protect against the advancement of CKD.

Resources

JCI
https://insight.jci.org/articles/view/132826

Mitophagy dependent macrophage reprogramming protects against kidney fibrosis.

JCI Insight

https://doi.org/10.1172/jci.insight.132826.

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-/- bone-marrow-derived macrophages (BMDMs) showed enhanced expression of rictor. Mitochondria from TGF-β1-treated Pink1-/- BMDMs exhibited increased superoxide levels, and reduced respiration and ATP production. In addition, mitophagy in macrophages involves PINK1-mediated phosphorylation of downstream MFN2 and 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 demonstrate that macrophage mitophagy plays a protective role against kidney fibrosis via regulating PINK1/MFN2/Parkin-mediated pathway.
October 2019
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