Mitochondria perform diverse yet interconnected functions, producing ATP and many biosynthetic intermediates while also contributing to cellular stress responses such as autophagy and apoptosis. Mitochondria form a dynamic, interconnected network that is intimately integrated with other cellular compartments. In addition, mitochondrial functions extend beyond the boundaries of the cell and influence an organism’s physiology by regulating communication between cells and tissues. It is therefore not surprising that mitochondrial dysfunction has emerged as a key factor in a myriad of diseases, including neurodegenerative and metabolic disorders. We provide a current view of how mitochondrial functions impinge on health and disease.

Mitochondrial structure and distribution are regulated by division and fusion events. Mitochondrial division is regulated by Dnm1/Drp1, a dynamin-related protein that forms helices around mitochondria to mediate fission. Little is known about what determines sites of mitochondrial fission within the mitochondrial network. The ER and mitochondria exhibit tightly coupled dynamics and have extensive contacts. We tested whether ER plays a role in mitochondrial division. We found that mitochondrial division occurred at positions where ER tubules contacted mitochondria and mediated constriction prior to Drp1 recruitment. Thus, ER tubules may play an active role in defining the position of mitochondrial division sites.

Communication between organelles is an important feature of all eukaryotic cells. To uncover components involved in mitochondria/endoplasmic reticulum (ER) junctions, we screened for mutants that could be complemented by a synthetic protein designed to artificially tether the two organelles. We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. The tethering complex was composed of proteins resident of both ER and mitochondria. With the use of genome-wide mapping of genetic interactions, we showed that the components of the tethering complex were functionally connected to phospholipid biosynthesis and calcium-signaling genes. In mutant cells, phospholipid biosynthesis was impaired. The tethering complex localized to discrete foci, suggesting that discrete sites of close apposition between ER and mitochondria facilitate interorganelle calcium and phospholipid exchange.Eukaryotic cells evolved segregation of functions into separate organelles. Compartmentalization increases the efficiency of biochemical reactions by creating tailored chemical microenvironments, but also creates a need for communication and routes of metabolite exchange. Membrane lipids, for example, are primarily synthesized in the endoplasmic reticulum (ER) and distributed to other organelles. Many organelles exchange phospholipids with the ER via vesicular transport. In contrast, mitochondria are not connected to vesicular trafficking pathways, and many lipids of the inner and outer mitochondrial Other work has implicated ER-mitochondrial contact sites in Ca ++ transport between the ER and mitochondria (4-6), suggesting a mechanism that may exploit the formation of an encapsulated space at the contact sites, akin to that formed at neuronal or immunological synapses. Such a connection between the ER and the mitochondria might buffer and control cytosolic and mitochondrial Ca ++ concentrations (7). Several proteins have been implicated to participate in ER-mitochondria contacts, including the ER resident Ca ++ channel IP3 receptor, the mitochondrial voltage-dependent anion channel, the chaperones grp75 and sigma-1R, the sorting protein PACS-2, and the mitofusin Mfn2 (8-11).To explore a role for ER-mitochondrial junctions, we sought mutants in the yeast Saccharomyces cerevisiae, in which tethering between the two organelles was impaired. We reasoned that, if such contacts are important, defects in proteins that establish these interactions would be detrimental, yet perhaps could be suppressed by artificially tethering ER and mitochondria (Fig. 1A). We designed a synthetic ER-mitochondria tether ("ChiMERA" for construct helping in mitochondria-ER association) (Fig. 1B) consisting of an N-terminal mitochondrial signal sequence and transmembrane domain derived from Tom70, a central module composed of green fluorescent protein (GFP), and a C-terminal ER tail-anchor derived from Ubc6. The design was based on a similar chimeric protein that strengthened mitochondria-ER interactions (12). The GFP moiet...

Mitochondria are one of the major ancient endomembrane systems in eukaryotic cells. Owing to their ability to produce ATP through respiration, they became a driving force in evolution. As an essential step in the process of eukaryotic evolution, the size of the mitochondrial chromosome was drastically reduced, and the behaviour of mitochondria within eukaryotic cells radically changed. Recent advances have revealed how the organelle’s behaviour has evolved to allow the accurate transmission of its genome and to become responsive to the needs of the cell and its own dysfunction.

Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases.