DRP1 regulates nucleoid segregation by modifying endoplasmic reticulum structure

Hema Saranya Ilamathi^1,2, Mathieu Ouellet^1,2,4, Justine Desrochers-Goyette^1,2, Matthew A Lines³, Marc Germain^1,2

¹Groupe de Recherche en Signalisation Cellulaire and Département de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada
²Centre d'Excellence en Recherche sur les Maladies Orphelines - Fondation Courtois, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada
³Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada
⁴Department of Electrical and Systems Engineering, University of Pennsylvania, Philadelphia, United States

Mitochondria are important organelles required for multiple metabolic activities including ATP production. To function, mitochondria require proteins coded by both nuclear and mitochondrial DNA (mtDNA). Mutations in either genome lead to an array of mitochondrial diseases, with mutations in nuclear genes affecting either a specific metabolic activity or mtDNA maintenance. mtDNA is organized into discrete nucleoprotein foci within mitochondria called nucleoids. Although the mechanism of mtDNA replication is well defined, the processes regulating segregation and distribution of nucleoids across the mitochondrial network are still unclear. Mitochondrial dynamics, the process by which mitochondria fuse and fragment to reorganize mitochondrial network in response to cues such as nutrient stress, has previously been suggested to regulate mtDNA. In fact, mitochondrial fusion is essential for mtDNA replication. On the other hand, while loss of mitochondrial fission causes nucleoid aggregation, its role in nucleoid segregation and distribution across the mitochondrial network are still unclear. Here, we show that the mitochondrial fission protein DRP1 regulates nucleoid segregation by altering the endoplasmic reticulum (ER) structure. Specifically, we found that the enlarged nucleoids present in DRP1 mutant primary human fibroblasts were spatially correlated with altered ER sheets. Further, loss of nucleoid segregation results in the enrichment of electron chain components at the site of enlarged nucleoids resulting in mosaic functioning of mitochondria. Overall, our data demonstrate that mitochondrial fission control nucleoid division through regulating ER structure, which in turn is crucial for proper functioning of mitochondria.