Interorganelle Communication, Aging, and Neurodegeneration

Downloaded from genesdev.cshlp.org on October 9, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Interorganelle communication, aging, and neurodegeneration Maja Petkovic,1 Caitlin E. O’Brien,2 and Yuh Nung Jan1,2,3 1Department of Physiology, University of California at San Francisco, San Francisco, California 94158, USA; 2Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California 94158, USA; 3Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94158, USA Our cells are comprised of billions of proteins, lipids, and ular transport cannot account for the exchange of certain other small molecules packed into their respective subcel- biomolecules. For example, delivery of several classes of lip- lular organelles, with the daunting task of maintaining cel- ids from their site of synthesis in the endoplasmic reticu- lular homeostasis over a lifetime. However, it is becoming lum (ER) to their steady-state location is unaffected by increasingly evident that organelles do not act as autono- pharmacological and genetic manipulations that deplete mous discrete units but rather as interconnected hubs cellular ATP levels, disrupt vesicular transport, and alter that engage in extensive communication through mem- cytoskeletal dynamics (Kaplan and Simoni 1985; Vance brane contacts. In the last few years, our understanding et al. 1991; Hanada et al. 2003; Baumann et al. 2005; Lev of how these contacts coordinate organelle function has re- 2012). Moreover, intracellular compartments like the ER defined our view of the cell. This review aims to present and mitochondria refill their depleted calcium (Ca2+) stores novel findings on the cellular interorganelle communica- through low-affinity calcium channels that require much tion network and how its dysfunction may contribute to higher local concentrations of calcium than global cytosol- aging and neurodegeneration. The consequences of dis- ic Ca2+ levels (Jousset et al. 2007; Carrasco and Meyer 2011). turbed interorganellar communication are intimately These findings raise the question about the existence of linked with age-related pathologies. Given that both aging other communication pathways such as direct contacts be- and neurodegenerative diseases are characterized by the tween organelles, and between intracellular compartments concomitant failure of multiple cellular pathways, coordi- and the plasma membrane. nation of organelle communication and function could Such “intimate associations” were observed already in represent an emerging regulatory mechanism critical for the 1950s in meticulous electron microscopy studies (Por- long-term cellular homeostasis. We anticipate that defin- ter and Palade 1957; Rosenbluth 1962). However, without ing the relationships between interorganelle communi- an established physiological relevance and known molecu- cation, aging, and neurodegeneration will open new lar components, such observations were mainly disregard- avenues for therapeutics. ed as artifacts, a consequence of a dense cellular environment or a feature only of highly specialized cells. It was not until a seminal paper by Jean Vance in 1990 that the first function of contact sites was reported. Using Interorganelle contacts, a historical perspective purified subcellular fractions of ER mitochondria-associated membranes, named MAM, she established these organ- Eukaryotic cells are defined by the presence of multiple in- elle contacts between the ER and mitochondria as sites of tracellular organelles, each specialized for a unique func- lipid synthesis and transfer (Vance 1990). A few years later, tion, that collectively coordinate the cell’s response to MAMs were implicated as sites of Ca2+ homeostasis (Riz- external and internal changes to sustain life. To do so, an or- zuto et al. 1998). It became apparent that organelles often ganelle communicates with its environment by importing form such contact sites, defined as specialized microdo- and exporting material through membrane transporters, mains of close apposition within the range of protein–pro- as well as by exchanging material with other organelles tein interactions that allow for coordination of organellar through vesicular transport. However, mitochondria, per- functions without organelle fusion. The identification of oxisomes, and plastids are not connected to major vesicular proteins mediating such interorganelle contacts was the transport systems (Sugiura et al. 2014). Furthermore, vesic- next leap for the field, with those mediating ER-mitochondria contacts identified first. The mitofusins were found to [Keywords: aging; cellular homeostasis; communication; contact sites; form contacts required for Ca2+ homeostasis (de Brito and endolysosomal pathway; interorganelle communication; lipid metabolism; mitochondria; neurodegeneration] Corresponding authors: [email protected], [email protected] © 2021 Petkovic et al. This article, published in Genes & Development, Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.346759. is available under a Creative Commons License (Attribution-NonCom- 120. Freely available online through the Genes & Development Open Ac- mercial 4.0 International), as described at http://creativecommons.org/ cess option. licenses/by-nc/4.0/. GENES & DEVELOPMENT 35:449–469 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/21; www.genesdev.org 449 Downloaded from genesdev.cshlp.org on October 9, 2021 - Published by Cold Spring Harbor Laboratory Press Petkovic et al. Scorrano 2008), while the multisubunit ERMES (ER-mito- Aging and age-related pathology as a consequence chondria encounter structure) complex is required for phos- of disturbed interorganelle communication pholipid biosynthesis (Kornmann et al. 2009). Today, the steady discovery of novel interoganelle contacts, the pro- Communication between organelles allows them to func- teins that mediate them, and their function has brought tion and adapt to changing cellular environments to main- ’ this field from obscurity to center stage. An exhaustive de- tain cellular homeostasis. The gradual failure of the cell s scription of all contact sites and the proteins that regulate ability to maintain homeostasis leads to physiological ag- them is well beyond the scope of this review, and the inter- ing and age-related pathologies like neurodegenerative ested reader is referred to many excellent reviews that pro- diseases. Decades of research have identified the mecha- vide detailed analyses of this topic (Eisenberg-Bord et al. nisms underlying physiological aging with relevance to 2016; Scorrano et al. 2019). Our apologies to colleagues pathological aging, which include dysregulated nutrient whose work we did not highlight in this review. sensing, dysfunctional bioenergetics, defective protein quality control and degradation, the seeding and propaga- tion of stress granules, and maladaptive innate immune responses (López-Otín et al. 2013; Gan et al. 2018). Only The redefined view of the cell as interconnected network more recently has interorganelle communication been The current view of the cell is that interorganelle commu- implicated in many of these processes: proper functioning nication through contact sites is ubiquitous across all eu- of lipid metabolism, mitochondrial function, and endoly- karyotic organisms, cell types, and organelles (Gatta and sosomal function. Here we highlight novel findings that Levine 2017). While originally called membrane contact link defects of interorganelle communication to aging sites, monobilayer organelles like lipid droplets, as well and neurodegeneration. While the loss of very few genes as nonmembranous organelles like RNA granules (Liao involved in contact sites is developmentally lethal, sever- et al. 2019) or stress granules (Lee et al. 2020), also engage al genes associated with age-related pathologies have in interorganelle communication. It has been proposed been directly linked to the failure of distinct contact sites, “ that contact sites predate vesicular trafficking, emerging as we elaborate on in Contact Sites Directly Linked with ” early in eukaryotic cells where they could have played a Aging and Neurodegeneration, below (Fig. 1). Likewise, crucial role in the acquisition of bacteria-type lipids the morphology and physiology of contact sites is per- from protomitochondria by their archaeal host (Jain and turbed in a variety of age-related neurodegenerative dis- “ Holthuis 2017). As eukaryotes evolved to contain the eases, as we discuss in Contribution of Dysfunctional full suite of organelles we recognize today, so did the con- Interorganelle Communication to Aging and Neurode- ” tacts between them also evolve to facilitate an increasing generation, below (Fig. 6, below). While there is still number of functions. For example, organelles exert phys- more work needed to disentangle whether these contact ical forces on each other (Helle et al. 2017; Feng and Korn- site disturbances are a cause or consequence of disease, mann 2018), and in the dense intracellular environment, these correlative observations suggest that coordination contact sites may have evolved to harness those forces of organelle communication at sites of contact could be for organelle remodeling, determining the sites of fission an emerging regulatory mechanism for long-term cellular for endosomes and mitochondria (Friedman et al. 2011; homeostasis. Because contact sites allow for

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