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

Hema Saranya Ilamathi; Sara Benhammouda; Amel Lounas; Khalid Al-Naemi; Justine Desrochers-Goyette; Matthew A Lines; François J Richard; Jackie Vogel; Marc Germain

doi:10.1016/j.isci.2023.107180

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

iScience. 2023 Jun 19;26(7):107180. doi: 10.1016/j.isci.2023.107180. eCollection 2023 Jul 21.

Authors

Hema Saranya Ilamathi^{1

2

3}, Sara Benhammouda^{1

2

3}, Amel Lounas⁴, Khalid Al-Naemi⁵, Justine Desrochers-Goyette^{1

2

3}, Matthew A Lines⁶, François J Richard⁴, Jackie Vogel⁵, Marc Germain^{1

2

3}

Affiliations

¹ Groupe de Recherche en Signalisation Cellulaire and Département de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada.
² Centre d'Excellence en Recherche sur les Maladies Orphelines - Fondation Courtois, Université du Québec à Montréal, Montréal, QC, Canada.
³ Réseau Intersectoriel de Recherche en Santé de l'Université du Québec (RISUQ), Laval, QC, Canada.
⁴ Centre de Recherche en Reproduction, Développement et Santé Intergénérationnelle (CRDSI), Département des Sciences Animales, Faculté des Sciences de L'agriculture et de L'alimentation, Université Laval, Québec, QC, Canada.
⁵ Department of Biology, McGill University, Montréal, QC, Canada.
⁶ Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Abstract

Mitochondria are multifaceted organelles crucial for cellular homeostasis that contain their own genome. Mitochondrial DNA (mtDNA) replication is a spatially regulated process essential for the maintenance of mitochondrial function, its defect causing mitochondrial diseases. mtDNA replication occurs at endoplasmic reticulum (ER)-mitochondria contact sites and is affected by mitochondrial dynamics: The absence of mitochondrial fusion is associated with mtDNA depletion whereas loss of mitochondrial fission causes the aggregation of mtDNA within abnormal structures termed mitobulbs. Here, we show that contact sites between mitochondria and ER sheets, the ER structure associated with protein synthesis, regulate mtDNA replication and distribution within mitochondrial networks. DRP1 loss or mutation leads to modified ER sheets and alters the interaction between ER sheets and mitochondria, disrupting RRBP1-SYNJ2BP interaction. Importantly, mtDNA distribution and replication were rescued by promoting ER sheets-mitochondria contact sites. Our work identifies the role of ER sheet-mitochondria contact sites in regulating mtDNA replication and distribution.

Keywords: Biochemistry; Biological sciences; Cell biology.