Contact sites between endoplasmic reticulum sheets and mitochondria regulate mitochondrial DNA replication and segregation

Abstract

Mitochondria are multi-faceted organelles crucial for cellular homeostasis that contain their own genome. Mitochondrial DNA (mtDNA) codes for several essential components of the electron transport chain, and mtDNA maintenance defects lead to mitochondrial diseases. mtDNA replication occurs at endoplasmic reticulum (ER)-mitochondria contact sites and is regulated by mitochondrial dynamics. Specifically, mitochondrial fusion is essential for mtDNA maintenance. In contrast, while loss of mitochondrial fission causes the aggregation of nucleoids (mtDNA-protein complexes), its role in nucleoid distribution remains unclear. Here, we show that the mitochondrial fission protein DRP1 regulates nucleoid segregation by altering ER sheets, the ER structure associated with protein synthesis. Specifically, DRP1 loss or mutation leads to altered ER sheets that physically interact with mitobulbs, mitochondrial structures containing aggregated nucleoids. Importantly, nucleoid distribution and mtDNA replication were rescued by expressing the ER sheet protein CLIMP63. Thus, our work identifies a novel mechanism by which DRP1 regulates mtDNA replication and distribution.

ER as master regulator of membrane trafficking and organelle function

“…Subpopulations of ER–mitochondria contact sites have been shown to be specifically reserved for and required for the synthesis of mtDNA ( Lewis et al, 2016 ). Following duplication of the nucleoid, DRP1 regulates the mtDNA synthesis and the distribution to the daughter organelles during fission by altering the ER sheets that contact the mitochondria ( Ilamathi et al, 2022 ; Lewis et al, 2016 ).…”

Connection Between HIV and Mitochondria in Cardiovascular Disease and Implications for Treatments

“…Critically, disruptions in these contact sites caused by DRP1 (dynamin-related protein 1; a mitochondrial fission protein), loss, or mutation affecting mtDNA replication and distribution, aid in determining protein synthesis and mtDNA spatial distribution. 153 Together, this underscores the importance of considering mitochondria as interconnected organelles with dysfunction manifesting in pleiotropic ways that typically include alterations in contact sites and dynamics.…”

“…Cumulative changes in mtDNA during HIV infection may in turn have regulatory effects across the rest of the mitochondria, including governing mitochondrial dynamics and organelle contact sites, 153 both of which remain poorly understood in the context of HIV. Since contact sites facilitate nucleoid division and segmentation, 128 it is important to study how nucleoids may concomitantly change with contact sites in HIV.…”

Redox regulation of UPR signalling and mitochondrial ER contact sites

“…On mitochondria PINK1 phosphorylates MFN2, recruits Parkin at the MERCS, allowing Parkin dependent ubiquitination of ER MFN2, promoting the separation of the two organelles and the initiation of mitophagy [196]. Release of mtDNA through channels such as VDAC (located in or close to MERCS) has emerged as a potential regulator for the inflammatory response [201] DRP1 [201,202]. Disruption of mitochondrial dynamics and subsequently mtDNA replication, may result in the release of mtDNA into the cytoplasm and in the generation of an inflammatory response [203,204].…”

“…Disruption of mitochondrial dynamics and subsequently mtDNA replication, may result in the release of mtDNA into the cytoplasm and in the generation of an inflammatory response [203,204]. Considering that the release of mtDNA is thought to occur through channels such VDAC (located in or close to MERCS), and as MFN2 mediates the tethering of ER with mitochondria, contact sites between these two organelles emerge as a potential regulator of the inflammatory response [201] (Fig. 4).…”