Promoting mitochondrial dynamics by inhibiting the PINK1–PRKN pathway to relieve diabetic nephropathy

Author:

Zhu Jun-yi12ORCID,van de Leemput Joyce12ORCID,Han Zhe12ORCID

Affiliation:

1. University of Maryland School of Medicine 1 Center for Precision Disease Modeling, Department of Medicine , , Baltimore, MD 21201 , USA

2. University of Maryland School of Medicine 2 Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine , , Baltimore, MD 21201 , USA

Abstract

ABSTRACT Diabetes is a metabolic disorder characterized by high blood glucose levels and is a leading cause of kidney disease. Diabetic nephropathy has been attributed to dysfunctional mitochondria. However, many questions remain about the exact mechanism. The structure, function and molecular pathways are highly conserved between mammalian podocytes and Drosophila nephrocytes; therefore, we used flies on a high-sucrose diet to model type 2 diabetic nephropathy. The nephrocytes from flies on a high-sucrose diet showed a significant functional decline and decreased cell size, associated with a shortened lifespan. Structurally, the nephrocyte filtration structure, known as the slit diaphragm, was disorganized. At the cellular level, we found altered mitochondrial dynamics and dysfunctional mitochondria. Regulating mitochondrial dynamics by either genetic modification of the Pink1–Park (mammalian PINK1–PRKN) pathway or treatment with BGP-15, mitigated the mitochondrial defects and nephrocyte functional decline. These findings support a role for Pink1–Park-mediated mitophagy and associated control of mitochondrial dynamics in diabetic nephropathy, and demonstrate that targeting this pathway might provide therapeutic benefits for type 2 diabetic nephropathy.

Funder

National Kidney Foundation

National Institutes of Health

Publisher

The Company of Biologists

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