Abstract
Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) serve as essential hubs for interorganelle communication in eukaryotic cells and play multifunctional roles in various biological pathways. A defect in ER-mitochondria signaling or MAMs dysfunction has pleiotropic effects on a variety of intracellular events, which results in disturbances of the mitochondrial quality control system, Ca2+ dyshomeostasis, apoptosis, ER stress, and inflammasome activation, which all contribute to the onset and progression of kidney disease. Here, we review the structure and molecular compositions of MAMs as well as the experimental methods used to study these interorganellar contact sites. We will specifically summarize the downstream signaling pathways regulated by MAMs, mainly focusing on mitochondrial quality control, oxidative stress, ER-mitochondria Ca2+ crosstalk, apoptosis, inflammasome activation, and ER stress. Finally, we will discuss how alterations in MAMs integrity contribute to the pathogenesis of kidney disease and offer directions for future research.
Highlights
Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and the leading cause of end stage renal disease (ESRD) in the United States and China [1, 2]
While the impacts of ER and mitochondrial dysfunction in DKD have largely been viewed and studied independently, the mitochondria and ER membranes physically interact with each other at specific subdomains termed mitochondrion-associated endoplasmic reticulum membranes (MAMs) that are functionally involved in the modulation of interorganellar Ca2+ exchange [7, 8], mitochondrial dynamics [9], inflammasome assembly [10], activation of autophagy/mitophagy [11,12,13], redox signaling control [14], and ER stress [15], and each of these processes has been reported to be involved in the occurrence and progression of DKD
Subsequent studies have further confirmed that ER-localized inverted formin 2- (INF2-) induced actin polymerization at MAMs may serve as the impetus for initial mitochondrial constriction and division by two independent mechanisms [83, 86]: (1) actin polymerization constricts the mitochondrial tubule sufficiently to fit its diameter to that of Drp1 oligomerization, leading to OMM constriction and (2) actin polymerization resulting in MAMs formation facilitates calcium transfer from the ER to the mitochondrion, triggering IMM constriction
Summary
Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and the leading cause of end stage renal disease (ESRD) in the United States and China [1, 2]. While the impacts of ER and mitochondrial dysfunction in DKD have largely been viewed and studied independently, the mitochondria and ER membranes physically interact with each other at specific subdomains termed mitochondrion-associated endoplasmic reticulum membranes (MAMs) that are functionally involved in the modulation of interorganellar Ca2+ exchange [7, 8], mitochondrial dynamics [9], inflammasome assembly [10], activation of autophagy/mitophagy [11,12,13], redox signaling control [14], and ER stress [15], and each of these processes has been reported to be involved in the occurrence and progression of DKD These facts indicate that changes in MAMs may underlie many of the phenotypes that control the pathological progression of kidney disease. This review is aimed at filling the gap towards kidney diseases to lay a foundation for future studies building on existing data
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