Cytological and biochemical analyses show that Ylr072w, here renamed Lipid transfer at contact site 1 (Ltc1), is a sterol transport protein localized to both ER–mitochondria and ER–vacuole contact sites in partnership with the organelle-specific components Tom70/81 and Vac8, respectively.
To elucidate the functional roles of mitochondrial dynamics in vivo, we identified genes that become essential in cells lacking the dynamin-related proteins Fzo1 and Dnm1, which are required for mitochondrial fusion and division, respectively. The screen identified Num1, a cortical protein implicated in mitochondrial division and distribution that also functions in nuclear migration. Our data indicate that Num1, together with Mdm36, forms a physical tether that robustly anchors mitochondria to the cell cortex but plays no direct role in mitochondrial division. Our analysis indicates that Num1-dependent anchoring is essential for distribution of the static mitochondrial network in fzo1 dnm1 cells. Consistently, expression of a synthetic mitochondria-cortex tether rescues the viability of fzo1 dnm1 num1 cells. We find that the cortical endoplasmic reticulum (ER) also is a constituent of the Num1 mitochondria-cortex tether, suggesting an active role for the ER in mitochondrial positioning in cells. Thus, taken together, our findings identify Num1 as a key component of a mitochondria-ER-cortex anchor, which we termed "MECA," that functions in parallel with mitochondrial dynamics to distribute and position the essential mitochondrial network.T he shape and cellular distribution of mitochondria depend on the integrated and regulated activities of mitochondrial division and fusion, motility, and tethering (1). A key question is how these mitochondrial behaviors are coordinated to shape and position mitochondria properly in response to the changing needs of the cell. To begin to address this question, an understanding of the molecular basis of mitochondrial behaviors is essential.The molecular mechanisms underlying mitochondrial division and fusion are best understood in terms of mitochondrial behaviors (1, 2). At the heart of the molecular machines that mediate mitochondrial division and fusion are dynamin-related proteins (DRPs) that function via GTP-dependent self-assembly and GTP hydrolysismediated conformational changes to remodel membranes. The DRP Dnm1/DRP1 (in yeast and mammals, respectively) drives the scission of mitochondrial membranes, and the DRPs Fzo1/ MFN1/2 and Mgm1/OPA1 mediate fusion of the outer and inner mitochondrial membranes, respectively. The relative rates of mitochondrial division and fusion are major determinants of the steadystate structure of the organelle and greatly influence its distribution. Attenuation of mitochondrial division leads to a more interconnected, collapsed, and less distributable mitochondrial network, and attenuation of mitochondrial fusion results in mitochondrial fragmentation and pronounced defects in the transmission and distribution of mtDNA.Although mitochondrial division and fusion are important, additional parallel pathways also are likely to be important for mitochondrial distribution. For example, the stable positioning of mitochondria at specific cellular locations, an indication of active tethering mechanisms, has been observed in many different cell types. In ...
Mitochondrial division is important for mitochondrial distribution and function. Recent data have demonstrated that ER–mitochondria contacts mark mitochondrial division sites, but the molecular basis and functions of these contacts are not understood. Here we show that in yeast, the ER–mitochondria tethering complex, ERMES, and the highly conserved Miro GTPase, Gem1, are spatially and functionally linked to ER-associated mitochondrial division. Gem1 acts as a negative regulator of ER–mitochondria contacts, an activity required for the spatial resolution and distribution of newly generated mitochondrial tips following division. Previous data have demonstrated that ERMES localizes with a subset of actively replicating mitochondrial nucleoids. We show that mitochondrial division is spatially linked to nucleoids and that a majority of these nucleoids segregate prior to division, resulting in their distribution into newly generated tips in the mitochondrial network. Thus, we postulate that ER-associated division serves to link the distribution of mitochondria and mitochondrial nucleoids in cells.DOI: http://dx.doi.org/10.7554/eLife.00422.001
Mitochondria are ancient organelles evolved from bacteria. Over the course of evolution, the behavior of mitochondria inside eukaryotic cells has changed dramatically, and the corresponding machineries that control it are in most cases new inventions. The evolution of mitochondrial behavior reflects the necessity to create a dynamic compartment to integrate the myriad mitochondrial functions with the status of other endomembrane compartments, such as the endoplasmic reticulum, and with signaling pathways that monitor cellular homeostasis and respond to stress. Here we review what has been discovered about the molecular machineries that work together to control the collective behavior of mitochondria in cells, as well as their physiological roles in healthy and disease states.
The emergence of endomembrane systems was a pivotal event in the evolution of the eukaryotic cell. Two ancient and fundamental, but evolutionarily distinct, eukaryotic endomembrane systems are mitochondria and the endoplasmic reticulum (ER). Both of these compartments are actively shaped into an extended reticular network, which enables them to communicate with each other and with other organelles distributed throughout the cell. Active protein-, lipid-, and ion-meditated interorganellar communication between mitochondria and the ER occur at points of contact at a distance of 10–30 nm between the two organelles. Recent advances, made primarily in budding yeast, have begun to describe the molecular features and mechanisms that underlie ER-mitochondria contact site formation and function. These and other studies have revealed that mitochondria make contacts with multiple organelles that possess functions beyond lipid and ion exchange. A more general model has emerged in which ion and lipid transport at interorganellar contacts sites also serve to form specialized microdomains that coordinate diverse activities, such as mitochondrial dynamics with cell stress signaling pathways. Here we highlight advances demonstrating the functional integration of activities at mitochondrial contact sites and speculate on how the functional outputs of different types of contact sites are somehow coordinated with each other and non-mitochondrial membrane contacts and pathways in the cell.
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