New horizons in mitochondrial contact site research

Abstract

<jats:title>Abstract</jats:title><jats:p>Contact sites, areas where two organelles are held in close proximity through the action of molecular tethers, enable non-vesicular communication between compartments. Mitochondria have been center stage in the contact site field since the discovery of the first contact between mitochondria and the endoplasmic reticulum (ER) over 60 years ago. However, only now, in the last decade, has there been a burst of discoveries regarding contact site biology in general and mitochondrial contacts specifically. The number and types of characterized contacts increased dramatically, new molecular mechanisms enabling contact formation were discovered, additional unexpected functions for contacts were shown, and their roles in cellular and organismal physiology were emphasized. Here, we focus on mitochondria as we highlight the most recent developments, future goals and unresolved questions in the field.</jats:p>

ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria

“…In mammalian cells, multiple tethering molecules have been suggested to act at contact sites between the ER and mitochondria [82]. For example, a single recent split proximity labeling approach proposed that 30 proteins are enriched in ER mitochondrial contact zones [83], but the individual functions of these factors still need to be elucidated; however, there is no doubt that these contacts are highly important for cellular functionality [84,85].…”

The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis

“…This effect may be cell-specific, as it was not observed in HeLa cells [95]. Considering the multiplicity of proteins that act as tethers between the two organelles [11,128], ã 40% reduction is an impressive effect. Depletion of VAPB or PTPIP51 had similar effects, and PTPIP51 silencing reduced the amount of VAPB recovered in a mitochondria plus MAM subcellular fraction, suggesting that PTPIP51 is VAPB's major partner on the outer mitochondrial membrane of MNs [60,61].…”

“…The elucidation of the roles of ER-mitochondria contacts in lipid transport and Ca 2+ regulation was followed by the discovery of additional functions of these contacts [128], and the identification of proteins that link the two organelles. In yeast, an elegant genetic screen led to the discovery of the ERMES complex (ER-mitochondrial encounter structure) [129].…”

“…In yeast, an elegant genetic screen led to the discovery of the ERMES complex (ER-mitochondrial encounter structure) [129]. This structure is not present in higher eukaryotes, but intensive research has uncovered many other tethering complexes, which may have specific roles in the different processes governed by ER-mitochondria contacts (reviews: [11,128]). Of the numerous complexes identified so far, four contain the VAPs linked to different FFAT-containing proteins on the mitochondrial surface, specifically: protein tyrosine phosphatase-interacting protein 51 (PTPIP51) [60], vacuolar protein sorting (VPS) 13A/ D [42,59,130], and mitoguardin 2 (MIGA2) [65,66] (see Table 1).…”

SEA and GATOR 10 Years Later

“…npr2∆ and npr3∆ yeast strains failed to activate the retrograde signaling pathway when grown in media containing ammonia as nitrogen source [10,148]. In order to recruit the substrates for reactions and export resulting products mitochondria rely on direct transport with organelles through contact sites [154]. The vacuole and mitochondria contact sites, vCLAMPs, are important for lipid exchange [155] and may also serve for the sensing of the integrity and functionality of mitochondria (Figure 4) [135].…”