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 contact sites between mitochondria and ER sheets, the ER structure associated with protein synthesis, regulate mtDNA replication and nucleoid distribution within mitochondrial networks. Specifically, DRP1 loss or mutation leads to altered ER sheets and enhanced physical interaction 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 role of ER sheets-mitochondria contact sites in regulating mtDNA replication and distribution.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
We have added SIM and FIB-SEM data to further support the changes ER sheets we observe in DRP1 mutant cells. We have also completely reorder the manuscript and changed the title.
