Interaction Between Mitochondrial DNA Variants and Mitochondria/Endoplasmic Reticulum Contact Sites: A Perspective Review

Abstract

Mitochondria contain their own genome, mitochondrial DNA (mtDNA), essential to support their fundamental intracellular role in ATP production and other key metabolic and homeostatic pathways. Mitochondria are highly dynamic organelles that communicate with all the other cellular compartments, through sites of high physical proximity. Among all, their crosstalk with the endoplasmic reticulum (ER) appears particularly important as its derangement is tightly implicated with several human disorders. Population-specific mtDNA variants clustered in defining the haplogroups have been shown to exacerbate or mitigate these pathological conditions. The exact mechanisms of the mtDNA background-modifying effect are not completely clear and a possible explanation is the outcome of mitochondrial efficiency on retrograde signaling to the nucleus. However, the possibility that different haplogroups shape the proximity and crosstalk between mitochondria and the ER has never been proposed neither investigated. In this study, we pose and discuss this question and provide preliminary data to answer it. Besides, we also address the possibility that single, disease-causing mtDNA point mutations may act also by reshaping organelle communication. Overall, this perspective review provides a theoretical platform for future studies on the interaction between mtDNA variants and organelle contact sites.

Chemical Modulation of Mitochondria–Endoplasmic Reticulum Contact Sites

“…Indeed, it has been recently shown that livers from obese mice are characterized by overexpression of phosphofurin acidic cluster sorting protein (PACS2) and IP3R and by enhanced Ca 2+ -related MERCs function, and that insulin sensitivity can be ameliorated upon downregulation of these two proteins [52,54]. Although apparently contradictory, these results could be explained by the use of different experimental models (e.g., likely with different genetic background, potentially also impacting MERCs [55]) and by the fact that the analysis was performed in tissues with different metabolic requirements. In any case, these lines of evidence highlight the fact that interaction between the ER and mitochondria contributes to insulin and/or glucose signaling in liver and insulin-sensitive peripheral tissues.…”

Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease

“…Notably, in those disorders, altered MAM was associated with impaired bioenergetic output [ 17 , 18 , 54 ]. However, there is almost no information on the opposite possibility, namely, whether perturbed bioenergetics can affect MAM function [ 20 , 55 ]. We now show that, in fact, cells with deficiencies in OxPhos show perturbed MAM functions, but surprisingly, not in a uniform way.…”