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Mitochondria-Associated Membranes As Networking Platforms and Regulators of Cancer Cell Fate.

ABSTRACT: The tight cross talk between two essential organelles of the cell, the endoplasmic reticulum (ER) and mitochondria, is spatially and functionally regulated by specific microdomains known as the mitochondria-associated membranes (MAMs). MAMs are hot spots of Ca2+ transfer between the ER and mitochondria, and emerging data indicate their vital role in the regulation of fundamental physiological processes, chief among them mitochondria bioenergetics, proteostasis, cell death, and autophagy. Moreover, and perhaps not surprisingly, it has become clear that signaling events regulated at the ER-mitochondria intersection regulate key processes in oncogenesis and in the response of cancer cells to therapeutics. ER-mitochondria appositions have been shown to dynamically recruit oncogenes and tumor suppressors, modulating their activity and protein complex formation, adapt the bioenergetic demand of cancer cells and to regulate cell death pathways and redox signaling in cancer cells. In this review, we discuss some emerging players of the ER-mitochondria contact sites in mammalian cells, the key processes they regulate and recent evidence highlighting the role of MAMs in shaping cell-autonomous and non-autonomous signals that regulate cancer growth.

SUBMITTER: Sassano ML

PROVIDER: S-EPMC5563315 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Mitochondria-Associated Membranes As Networking Platforms and Regulators of Cancer Cell Fate.

Sassano Maria Livia ML van Vliet Alexander R AR Agostinis Patrizia P

Frontiers in oncology 20170818

The tight cross talk between two essential organelles of the cell, the endoplasmic reticulum (ER) and mitochondria, is spatially and functionally regulated by specific microdomains known as the mitochondria-associated membranes (MAMs). MAMs are hot spots of Ca<sup>2+</sup> transfer between the ER and mitochondria, and emerging data indicate their vital role in the regulation of fundamental physiological processes, chief among them mitochondria bioenergetics, proteostasis, cell death, and autopha ...[more]

PMID: 28868254

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Project description:BackgroundDiabetes is associated with an increased risk of cognitive decline and dementia. These diseases are linked with mitochondrial dysfunction, most likely as a consequence of excessive formation of mitochondria-associated membranes (MAMs). Sirtuin3 (SIRT3), a key mitochondrial NAD+-dependent deacetylase, is critical responsible for mitochondrial functional homeostasis and is highly associated with neuropathology. However, the role of SIRT3 in regulating MAM coupling remains unknown.MethodsStreptozotocin-injected diabetic mice and high glucose-treated SH-SY5Y cells were established as the animal and cellular models, respectively. SIRT3 expression was up-regulated in vivo using an adeno-associated virus in mouse hippocampus and in vitro using a recombinant lentivirus vector. Cognitive function was evaluated using behavioural tests. Hippocampus injury was assessed using Golgi and Nissl staining. Apoptosis was analysed using western blotting and TUNEL assay. Mitochondrial function was detected using flow cytometry and confocal fluorescence microscopy. The mechanisms were investigated using co-immunoprecipitation of VDAC1-GRP75-IP3R complex, fluorescence imaging of ER and mitochondrial co-localisation and transmission electron microscopy of structural analysis of MAMs.ResultsOur results demonstrated that SIRT3 expression was significantly reduced in high glucose-treated SH-SY5Y cells and hippocampal tissues from diabetic mice. Further, up-regulating SIRT3 alleviated hippocampus injuries and cognitive impairment in diabetic mice and mitigated mitochondrial Ca2+ overload-induced mitochondrial dysfunction and apoptosis. Mechanistically, MAM formation was enhanced under high glucose conditions, which was reversed by genetic up-regulation of SIRT3 via reduced interaction of the VDAC1-GRP75-IP3R complex in vitro and in vivo. Furthermore, we investigated the therapeutic effects of pharmacological activation of SIRT3 in diabetic mice via honokiol treatment, which exhibited similar effects to our genetic interventions.ConclusionsIn summary, our findings suggest that SIRT3 ameliorates cognitive impairment in diabetic mice by limiting aberrant MAM formation. Furthermore, targeting the activation of SIRT3 by honokiol provides a promising therapeutic candidate for diabetes-associated cognitive dysfunction. Overall, our study suggests a novel role of SIRT3 in regulating MAM coupling and indicates that SIRT3-targeted therapies are promising for diabetic dementia patients.

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Mitochondria-Associated Membranes As Networking Platforms and Regulators of Cancer Cell Fate.

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Mitochondria-Associated Membranes As Networking Platforms and Regulators of Cancer Cell Fate.

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