Dataset Information

Forcing contacts between mitochondria and the endoplasmic reticulum extends lifespan in a Drosophila model of Alzheimer's disease.

ABSTRACT: Eukaryotic cells are complex systems containing internal compartments with specialised functions. Among these compartments, the endoplasmic reticulum (ER) plays a major role in processing proteins for modification and delivery to other organelles, whereas mitochondria generate energy in the form of ATP. Mitochondria and the ER form physical interactions, defined as mitochondria-ER contact sites (MERCs) to exchange metabolites such as calcium ions (Ca2+) and lipids. Sites of contact between mitochondria and the ER can regulate biological processes such as ATP generation and mitochondrial division. The interactions between mitochondria and the ER are dynamic and respond to the metabolic state of cells. Changes in MERCs have been linked to metabolic pathologies such as diabetes, neurodegenerative diseases and sleep disruption. Here we explored the consequences of increasing contacts between mitochondria and the ER in flies using a synthetic linker. We showed that enhancing MERCs increases locomotion and extends lifespan. We also showed that, in a Drosophila model of Alzheimer's disease linked to toxic amyloid beta (A?), linker expression can suppress motor impairment and extend lifespan. We conclude that strategies for increasing contacts between mitochondria and the ER may improve symptoms of diseases associated with mitochondria dysfunction. A video abstract for this article is available at https://youtu.be/_YWA4oKZkes.This article has an associated First Person interview with the first author of the paper.

SUBMITTER: Garrido-Maraver J

PROVIDER: S-EPMC6994956 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Forcing contacts between mitochondria and the endoplasmic reticulum extends lifespan in a <i>Drosophila</i> model of Alzheimer's disease.

Garrido-Maraver Juan J Loh Samantha H Y SHY Martins L Miguel LM

Biology open 20200114 1

Eukaryotic cells are complex systems containing internal compartments with specialised functions. Among these compartments, the endoplasmic reticulum (ER) plays a major role in processing proteins for modification and delivery to other organelles, whereas mitochondria generate energy in the form of ATP. Mitochondria and the ER form physical interactions, defined as mitochondria-ER contact sites (MERCs) to exchange metabolites such as calcium ions (Ca<sup>2+</sup>) and lipids. Sites of contact be ...[more]

PMID: 31822473

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Project description:SEPN1-related myopathy (SEPN1-RM) is a muscle disorder due to mutations of the SEPN1 gene, which is characterized by muscle weakness and fatigue leading to scoliosis and life-threatening respiratory failure. Core lesions, focal areas of mitochondria depletion in skeletal muscle fibers, are the most common histopathological lesion. SEPN1-RM underlying mechanisms and the precise role of SEPN1 in muscle remained incompletely understood, hindering the development of biomarkers and therapies for this untreatable disease. To investigate the pathophysiological pathways in SEPN1-RM, we performed metabolic studies, calcium and ATP measurements, super-resolution and electron microscopy on in vivo and in vitro models of SEPN1 deficiency as well as muscle biopsies from SEPN1-RM patients. Mouse models of SEPN1 deficiency showed marked alterations in mitochondrial physiology and energy metabolism, suggesting that SEPN1 controls mitochondrial bioenergetics. Moreover, we found that SEPN1 was enriched at the mitochondria-associated membranes (MAM), and was needed for calcium transients between ER and mitochondria, as well as for the integrity of ER-mitochondria contacts. Consistently, loss of SEPN1 in patients was associated with alterations in body composition which correlated with the severity of muscle weakness, and with impaired ER-mitochondria contacts and low ATP levels. Our results indicate a role of SEPN1 as a novel MAM protein involved in mitochondrial bioenergetics. They also identify a systemic bioenergetic component in SEPN1-RM and establish mitochondria as a novel therapeutic target. This role of SEPN1 contributes to explain the fatigue and core lesions in skeletal muscle as well as the body composition abnormalities identified as part of the SEPN1-RM phenotype. Finally, these results point out to an unrecognized interplay between mitochondrial bioenergetics and ER homeostasis in skeletal muscle. They could therefore pave the way to the identification of biomarkers and therapeutic drugs for SEPN1-RM and for other disorders in which muscle ER-mitochondria cross-talk are impaired.

Dataset Information

Forcing contacts between mitochondria and the endoplasmic reticulum extends lifespan in a Drosophila model of Alzheimer's disease.

Publications

Forcing contacts between mitochondria and the endoplasmic reticulum extends lifespan in a <i>Drosophila</i> model of Alzheimer's disease.

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