Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease.

Autor: Morcillo P; Department of Neurology, Columbia University Medical Center, New York, NY, 10032, USA. phd.morcillo@gmail.com., Kabra K; Department of Neurology, Columbia University Medical Center, New York, NY, 10032, USA., Velasco K; Department of Neurology, Columbia University Medical Center, New York, NY, 10032, USA., Cordero H; Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, 10032, USA.; Immunology Group, Department of Physiology, Faculty of Veterinary, University of Extremadura, Caceres, 10003, Spain., Jennings S; Stony Brook University, Stony Brook, New York, NY, 11794, USA., Yun TD; Department of Neurology, Columbia University Medical Center, New York, NY, 10032, USA., Larrea D; Department of Neurology, Columbia University Medical Center, New York, NY, 10032, USA., Akman HO; Department of Neurology, Columbia University Medical Center, New York, NY, 10032, USA., Schon EA; Department of Neurology, Columbia University Medical Center, New York, NY, 10032, USA. eas3@columbia.edu.; Department of Genetics and Development, Columbia University Medical Center, New York, NY, 10032, USA. eas3@columbia.edu.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Jun 10; Vol. 15 (6), pp. 405. Date of Electronic Publication: 2024 Jun 10.
DOI: 10.1038/s41419-024-06781-9
Abstrakt: Genetic mutations causing primary mitochondrial disease (i.e those compromising oxidative phosphorylation [OxPhos]) resulting in reduced bioenergetic output display great variability in their clinical features, but the reason for this is unknown. We hypothesized that disruption of the communication between endoplasmic reticulum (ER) and mitochondria at mitochondria-associated ER membranes (MAM) might play a role in this variability. To test this, we assayed MAM function and ER-mitochondrial communication in OxPhos-deficient cells, including cybrids from patients with selected pathogenic mtDNA mutations. Our results show that each of the various mutations studied indeed altered MAM functions, but notably, each disorder presented with a different MAM "signature". We also found that mitochondrial membrane potential is a key driver of ER-mitochondrial connectivity. Moreover, our findings demonstrate that disruption in ER-mitochondrial communication has consequences for cell survivability that go well beyond that of reduced ATP output. The findings of a "MAM-OxPhos" axis, the role of mitochondrial membrane potential in controlling this process, and the contribution of MAM dysfunction to cell death, reveal a new relationship between mitochondria and the rest of the cell, as well as providing new insights into the diagnosis and treatment of these devastating disorders.
(© 2024. The Author(s).)
Databáze: MEDLINE
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