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Review
. 2014 Jan 16;505(7483):335-43.
doi: 10.1038/nature12985.

Mitochondrial form and function

Jonathan R Friedman  1 , Jodi Nunnari  1
Affiliations
Review

Mitochondrial form and function

Jonathan R Friedman et al. Nature. .

Abstract

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.

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Figures

Figure 1
Figure 1. The organization and distribution of mitochondria and mtDNA in higher eukaryotes
Mitochondrial organization is a conserved feature. a, mtDNA in a human fibroblast is packaged within nucleoids (green) distributed within tubular mitochondria (red) around the nucleus (blue). Scale bar, 20 microns. Adapted with permission from ref. . b, A similar distribution is seen in a yeast cell with nucleoids (green) within mitochondria (red). Scale bar, 2 microns. c, Mitochondrial copy number is controlled by the combined actions of mitochondrial division and fusion. Mitochondrial division is controlled by the assembly of a dynamin-related protein (DRP) on the outside of the organelle into a helical structure, which mediates scission through interactions across helical rungs (marked by orange circles). Mitochondrial fusion is controlled by interactions of outer and inner membrane fusion DRPs (blue and red circles, respectively) across mitochondrial membranes.
Figure 2
Figure 2. Evolution of mitochondrial division site placement mechanisms
a, Roles of FtsZ and dynamin-related proteins (DRPs) in bacterial and endosymbiotic organelle division and division site placement. In the α-proteobacterial ancestor of mitochondria, an FtsZ ring is placed mid-cell by active mechanisms. The combined actions of the FtsZ-containing ring and cell-wall synthesis are essential for cell division. In chloroplasts and algal mitochondria, FtsZ-dependent placement (indicated by arrows) and division mechanisms on the inside of the organelle have been retained during evolution. However, in these organelles, DRPs also function on the cytosolic surface in organelle division, perhaps replacing the requirement for cell-wall synthesis in division. In yeast or animals, DRPs function on the cytosolic surface in organelle division. Before DRP recruitment, however, the endoplasmic reticulum (ER) is associated with division-site placement and constriction on the outside of the organelle, potentially replacing FtsZ-dependent placement and constriction. b, Molecular model for division site placement coupled to nucleoid segregation in yeast mitochondria. In yeast, the ER–mitochondria tethering complex, ER–mitochondrial encounter structure (ERMES), and the conserved Miro GTPase Gem1 are spatially and functionally linked to ER-associated mitochondrial division (ERMD). ERMD sites marked by these components are also spatially localized to a subset of nucleoids that are actively replicating, and these segregate before ERMD. Gem1 acts as a negative regulator of ERMES-dependent ER–mitochondria contacts and is required for the spatial resolution of newly generated mitochondria by ERMD, possibly through the localized recruitment of the actin cytoskeleton. Cytoskeletal components may also participate in ER-associated mitochondrial constriction before DRP recruitment. Nucleoid placement at sites of ERMD could be mediated by a mark inside the organelle formed by the scaffold MitOS complex. Mdm33 is a possible candidate for the internal membrane scission machine in yeast.
Figure 3
Figure 3. Integration of mitochondrial stress response pathways and their coordination with mitochondrial shape
Several different mitochondrial pathways respond to stress or damage and are coordinated with mitochondrial dynamics. Mitochondria in healthy cells generate an electrochemical potential that serves in oxidative phosphorylation and drives the import of proteins into the organelle. Damage that leads to a loss (blue) of mitochondrial membrane potential can lead to a loss of protein import efficiency. In the unfolded protein stress response (UPRmt) pathway, loss of import leads to the accumulation of the transcription factor ATFS1 in the nucleus, activating a transcriptional mitochondrial repair and metabolic adaptation response. Loss of membrane potential also triggers the OMA1-dependent proteolysis of long isoforms of the inner membrane fusion DRP OPA1, which attenuates mitochondrial fusion and potentially increases ER-mediated mitochondrial division (ERMD), resulting in mitochondrial fragmentation. These fragmented mitochondria that have lost the ability to respire and import may also accumulate the PINK1 kinase, which triggers mitophagy. In addition, under these conditions, the ERMD domain may be altered to directly promote BAX oligomerization on the mitochondrial outer membrane, outer-membrane permeabilization and cytochrome c release, leading to cell death. Mitochondrial dysfunction and stresses such as starvation can trigger mitochondrial hyperfusion, which is dependent on maintenance of mitochondrial membrane potential (red) and the presence of both long and short OPA1 isoforms. Hyperfused mitochondria can transiently buffer the effects of respiratory chain dysfunction and do not enter the mitophagy pathway. The relationship between UPRmt and mitochondrial shape has not been explored.
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