David Chan

..A better understanding of these processes likely will ultimately lead to improvements in human health...

..In this issue of Developmental Cell, DeLuca and O'Farrell (2012) show that active elimination of mtDNA during sperm development in Drosophila ensures that mature spermatozoa are devoid of DNA...

..These components play important roles in mitochondrial function and development as well as programmed cell death. Disruption of the fusion machinery leads to neurodegenerative disease...

..Clearly, much about the basic biology of mitochondria remains to be understood. Here we discuss recent work that suggests that the dynamics (fusion and fission) of these organelles is important in development and disease...

..Fusion of the outer membranes requires mitofusins. A new study published in Cell (Meeusen et al., 2006) shows that inner membrane fusion requires the dynamin-related protein Mgm1/OPA1...

..We highlight recent findings that have advanced our understanding of the mechanism, function, and regulation of mitochondrial fusion...

..Each of the null alleles disrupts the interaction of these two fragments, suggesting that we have identified a key interaction involving the GTPase domain and heptad repeats essential for fusion...

..2004 [this issue of Cell])...

..These studies provide insight into how mitochondria communicate with one another to coordinate mitochondrial function and morphology...

..With its dual function in safeguarding mtDNA integrity and preserving mtDNA function in the face of mutations, mitochondrial fusion is likely to be a protective factor in human disorders associated with mtDNA mutations...

..Such mtDNA defects lead to respiration-deficient mitochondria, and their accumulation in neurons leads to impaired outgrowth of cellular processes and ultimately neurodegeneration...

..These results indicate that mammalian mitofusins and OPA1 mediate distinct sequential fusion steps that are readily uncoupled, in contrast to the situation in yeast...

..We review how mitochondrial dynamics is altered in these neurodegenerative diseases and discuss the reciprocal interactions between mitochondrial fusion, fission, transport and mitophagy...

..This transgenic line recapitulates key motor features of CMT2A and provides a system to dissect the function of mitochondria in the axons of mammalian motor neurons...

..Cleavage at S2 is regulated by the i-AAA protease Yme1L. Our results suggest that mammalian cells have multiple pathways to control mitochondrial fusion through regulation of the spectrum of OPA1 isoforms...

....

..Our studies support a revised model for assembly of the mitochondrial fission apparatus...

..But what are the molecular mechanisms that control mitochondrial dynamics, and why are they important for mitochondrial function? We review these issues and explore how defects in mitochondrial dynamics might cause neuronal disease...

..Our results reveal how Fis1 recruits the mitochondrial fission complex and will facilitate efforts to manipulate mitochondrial fission...

..Therefore, mitochondrial fusion is essential for embryonic development, and by enabling cooperation between mitochondria, has protective effects on the mitochondrial population...

..Consistent with this proposal, truncated mitofusin, in an HR2-dependent manner, causes mitochondria to become apposed with a uniform gap. Our results suggest that HR2 functions as a mitochondrial tether before fusion...

..Furthermore, they suggest that tissues with low Mfn1 expression are vulnerable in CMT2A and that methods to increase Mfn1 expression in the peripheral nervous system would benefit CMT2A patients...

..Perhaps it is the strict spatial and functional requirements for mitochondria in neurons that cause defects in mitochondrial fusion to manifest primarily as neurodegenerative diseases...

..These results provide important structural information about this intermediate that should facilitate the development of HIV-1 entry inhibitors and may lead to new vaccine strategies...

..In contrast, fragmentation of mitochondria, without severe loss of fusion, did not result in such cellular defects. Our results showed that key cellular functions decline as mitochondrial fusion is progressively abrogated...

..These results provide evidence that gp41 hairpin stability is critical for mediating fusion and suggest a novel role for the glutamine layer in gp41 function...

..An understanding of the molecular mechanism of fusion may have implications for Charcot-Marie-Tooth subtype 2A and autosomal dominant optic atrophy, neurodegenerative diseases caused by mutations in Mfn2 and OPA1...

..Moreover, our findings suggest a novel basis for the mitochondrial fragmentation observed during apoptosis...

..The block in mitochondrial fusion occurs within the same time range as Bax coalescence on the mitochondria and outer mitochondrial membrane permeabilization, and it may be a consequence of Bax/Bak activation during apoptosis...

..Our results indicate the existence of a regulatory pathway involving PGC-1 alpha, ERR alpha, and Mfn2. Alterations in this regulatory pathway may participate in the pathophysiology of insulin-resistant conditions and type 2 diabetes...

..These studies will lead to an understanding of the pathogenesis CMT2A at the cellular and whole-animal level. In addition, they will likely impact the understanding of the pathogenesis of mitochondrial encephalomyopathies. ..

..These studies will lead to structural insights that will enable investigators to manipulate mitochondrial fission, and thereby potentially modulate processes such as apoptosis, cancer, and nerve function. ..

..These studies will lead to an understanding of the pathogenesis CMT2A at the cellular and whole-animal level. In addition, they will likely impact the understanding of the pathogenesis of mitochondrial encephalomyopathies. ..

..In addition to clarifying a basic cellular process, these studies may further understanding of human mitochondrial diseases and aging. ..

..These studies will lead to structural insights that will enable investigators to manipulate mitochondrial fission, and thereby potentially modulate processes such as apoptosis, cancer, and nerve function. ..