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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. [ABSTRACT FROM AUTHOR]

The mitochondrial intermembrane space (IMS) houses a large spectrum of proteins with distinct and critical functions. Protein import into this mitochondrial sub-compartment is underpinned by an intriguing variety of pathways, many of which are still poorly understood. The constricted volume of the IMS and the topological segregation by the inner membrane cristae into a bulk area surrounded by the boundary inner membrane and the lumen within the cristae is an important factor that adds to the complexity of the protein import, folding and assembly processes. We discuss the main import pathways into the IMS, but also how IMS proteins are degraded or even retro-translocated to the cytosol in an integrated network of interactions that is necessary to maintain a healthy balance of IMS proteins under physiological and cellular stress conditions. We conclude this review by highlighting new and exciting perspectives in this area with a view to develop a better understanding of yet unknown, likely unconventional import pathways, how presequence-less proteins can be targeted and the basis for dual localisation in the IMS and the cytosol. Such knowledge is critical to understanding the dynamic changes of the IMS proteome in response to stress, and particularly important for maintaining optimal mitochondrial fitness. [ABSTRACT FROM AUTHOR]

Endosymbiosis, the beginning of a collaboration between an archaeon and a bacterium and a founding step in the evolution of eukaryotes, owes its success to the establishment of communication routes between the host and the symbiont to allow the exchange of metabolites. As far as lipids are concerned, it is the host that has learnt the symbiont's language, as eukaryote lipids appear to have been borrowed from the bacterial symbiont. Mitochondria exchange lipids with the rest of the cell at membrane contact sites. In fungi, the endoplasmic reticulum-mitochondria encounter structure (ERMES) is one of the best understood membrane tethering complexes. Its discovery has yielded crucial insight into the mechanisms of intracellular lipid trafficking. Despite a wealth of data, our understanding of ERMES formation and its exact role(s) remains incomplete. Here, I endeavour to summarise our knowledge on the ERMES complex and to identify lingering gaps. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The mitochondrial intermembrane space (IMS) houses a large spectrum of proteins with distinct and critical functions. Protein import into this mitochondrial sub-compartment is underpinned by an intriguing variety of pathways, many of which are still poorly understood. The constricted volume of the IMS and the topological segregation by the inner membrane cristae into a bulk area surrounded by the boundary inner membrane and the lumen within the cristae is an important factor that adds to the complexity of the protein import, folding and assembly processes. We discuss the main import pathways into the IMS, but also how IMS proteins are degraded or even retro-translocated to the cytosol in an integrated network of interactions that is necessary to maintain a healthy balance of IMS proteins under physiological and cellular stress conditions. We conclude this review by highlighting new and exciting perspectives in this area with a view to develop a better understanding of yet unknown, likely unconventional import pathways, how presequence-less proteins can be targeted and the basis for dual localisation in the IMS and the cytosol. Such knowledge is critical to understanding the dynamic changes of the IMS proteome in response to stress, and particularly important for maintaining optimal mitochondrial fitness. [ABSTRACT FROM AUTHOR]

Endosymbiosis, the beginning of a collaboration between an archaeon and a bacterium and a founding step in the evolution of eukaryotes, owes its success to the establishment of communication routes between the host and the symbiont to allow the exchange of metabolites. As far as lipids are concerned, it is the host that has learnt the symbiont's language, as eukaryote lipids appear to have been borrowed from the bacterial symbiont. Mitochondria exchange lipids with the rest of the cell at membrane contact sites. In fungi, the endoplasmic reticulum-mitochondria encounter structure (ERMES) is one of the best understood membrane tethering complexes. Its discovery has yielded crucial insight into the mechanisms of intracellular lipid trafficking. Despite a wealth of data, our understanding of ERMES formation and its exact role(s) remains incomplete. Here, I endeavour to summarise our knowledge on the ERMES complex and to identify lingering gaps. [ABSTRACT FROM AUTHOR]