Interorganelle communication, aging, and neurodegeneration

Abstract

Our cells are comprised of billions of proteins, lipids, and other small molecules packed into their respective subcellular organelles, with the daunting task of maintaining cellular homeostasis over a lifetime. However, it is becoming increasingly evident that organelles do not act as autonomous discrete units but rather as interconnected hubs that engage in extensive communication through membrane contacts. In the last few years, our understanding of how these contacts coordinate organelle function has redefined our view of the cell. This review aims to present novel findings on the cellular interorganelle communication network and how its dysfunction may contribute to aging and neurodegeneration. The consequences of disturbed interorganellar communication are intimately linked with age-related pathologies. Given that both aging and neurodegenerative diseases are characterized by the concomitant failure of multiple cellular pathways, coordination of organelle communication and function could represent an emerging regulatory mechanism critical for long-term cellular homeostasis. We anticipate that defining the relationships between interorganelle communication, aging, and neurodegeneration will open new avenues for therapeutics.

Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain

“…Moreover, the exchange of metabolites and/or information between organelles is favoured by their physical proximity, thus making contact areas, i.e., MAM domains in the case of ERmitochondria contacts, the ideal hubs whereby key cellular tasks take place. Therefore, it is not surprising that alterations of organelle contacts and/or functionality have been associated with different pathological conditions, such as diabetes, cancer and neurodegeneration [27,40,[42][43][44][45]. In particular, increasing evidence suggests that disturbances in ER-mitochondria connectivity are early events in neurodegenerative disorders such as Parkinson's disease, amyotrophic lateral sclerosis and AD [46].…”

Cellular senescence links mitochondria-ER contacts and aging

“…The use of genetic mouse models targeting MERC components has highlighted MERCs importance in controlling various pathophysiological situations, ranging from vascular remodelling to inflammation and metabolic disorders 13 – 17 . More recently, a role of MERCs in aging was suggested by evidences showing a modulation of their quantity and quality with specific age-related diseases or aging 18 – 20 . While autophagy and apoptosis are proposed to mediate some of MERCs age-associated effects 18 , 19 , whether other critical mechanisms are also involved remains unclear.…”

“…specific age-related diseases or aging [18][19][20] . While autophagy and apoptosis are proposed to mediate some of MERCs age-associated effects 18,19 , whether other critical mechanisms are also involved remains unclear.…”

Nup358 regulates remodelling of ER-mitochondrial contact sites and autophagy

“…Consistent with the range of processes these contact sites regulate, dysfunctional ERMCS are implicated in many disorders including diabetes (Rieusset, 2018), cancers (Doghman-Bouguerra and Lalli, 2019;Peruzzo et al, 2020;Simoes et al, 2020) and neurodegeneration (Paillusson et al, 2016;Petkovic et al, 2021).…”

“…Contrary to the general perception that organelles in the cell exist and function independently, recent developments highlight that multiple organelles make physical and dynamic contacts with each other to coordinate the many functions they perform (Henne, 2016;Prinz et al, 2020;Scorrano et al, 2019;Wu et al, 2018). Endoplasmic reticulum (ER), an organelle characterized by its membranous network that extends throughout the cytoplasm, interacts with other organelles through specific contact sites (Cohen et al, 2018;López-Crisosto et al, 2015;Petkovic et al, 2021;Phillips and Voeltz, 2016). ER-mitochondria contact sites (ERMCS), also known as membrane-associated mitochondria (MAM), are maintained through physical interactions between proteins present on both the organelles (Marchi et al, 2014;Raturi and Simmen, 2013;Rowland and Voeltz, 2012;Wu et al, 2018) (Filadi et al, 2017).…”