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Freezing or Melting Mitochondria-ER Contacts (MERCs)
Thomas Simmen1, Junsheng Chen1, Megan Yap1, Klaus Ballanyi1, Jack Moore1, Helene Lemieux1, Xuejun Sun2.
1 University of Alberta, Edmonton, AB, Canada.
2 Cross Cancer Institute, Edmonton, AB, Canada.
Background: Mitochondria metabolism and lipidomics are under the control of membrane contact sites with the endoplasmic reticulum (ER). These contacts are biochemically known as mitochondria-associated membranes (MAMs) or mitochondria-ER contacts (MERCs). While numerous tethers are known to form this signaling platform (e.g., Mfn2, VAPB/PTPIP51, IP3R/VDAC), the control of their tethering function remains a topic of intense research, since MERCs undergo remodeling during ER stress or other changes of cell homeostasis. Our research has shown that ER stress “freezes” MERCs in a tight state, thus allowing for increased mitochondrial bioenergetics. This state requires increased production of reactive oxygen species (ROS) within the ER from NOX4 and ERO1. While ROS do not accumulate within the lumen of the ER, they are able to post-translationally modify tethers and their regulators (e.g., PERK). This then shifts tethering to its tight state, through increased binding of tether pairs.
Aims: The presentation will discuss the causes and effects of ROS on mitochondria-ER tethering. While increased ROS promotes tethering, their elimination “melts” MERCs and transforms these membrane contact sites into their loose state.
Methods: We assayed ROS levels in a variety of knockout and knockdown scenarios and mechanistically correlated their amounts to MERC formation and mitochondria metabolism.
Results: Our results show that NOX4 provides a baseline oxidation of MERC tethers and their regulators. Under ER stress, ERO1 is reassigned to provide ROS at mitochondrial membrane contact sites to oxidize PERK and promote tight tethering. ER transmembrane oxidoreductases of the TMX family can reverse this tight tethering and can moderate MERCs.
Conclusion: ER ROS production and elimination is a key controller of MERC remodeling, thus influencing ER-mitochondria calcium flux, lipidomics and mitochondria metabolism. A variety of ER protein folding-associated redox enzymes controls this redox-mediated metabolic signaling towards mitochondria. Therefore, ER oxidative protein folding emerges as a key upstream input for mitochondria biology.