Organization and dynamics of human mitochondrial DNA

Legros, Frédéric; Malka, Florence; Frachon, Paule; Lombès, Anne; Rojo, Manuel

doi:10.1242/jcs.01134

Cited by 339 publications

(264 citation statements)

References 42 publications

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“…2). Similar values have been reported for mt nucleoids in mosses, algae (2,17), and human cells (22,23), implying a structural similarity of mt nucleoids between these organisms.…”

Section: Discussionsupporting

confidence: 84%

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Active digestion of sperm mitochondrial DNA in single living sperm revealed by optical tweezers

Nishimura

Yoshinari

Naruse

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

144

104

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In almost all eukaryotes, mitochondrial (mt) genes are transmitted to progeny mainly from the maternal parent. The most popular explanation for this phenomenon is simple dilution of paternal mtDNA, because the paternal gametes (sperm) are much smaller than maternal gametes (egg) and contribute a limited amount of mitochondria to the progeny. Recently, this simple explanation has been challenged in several reports that describe the active digestion of sperm mtDNA, down-regulation of mtDNA replication in sperm, and proteolysis of mitochondria triggered by ubiquitination. In this investigation, we visualized mt nucleoids in living sperm by using highly sensitive SYBR green I vital staining. The ability to visualize mt nucleoids allowed us to clarify that the elimination of sperm mtDNA upon fertilization is achieved through two steps: (i) gradual decrease of mt nucleoid numbers during spermatogenesis and (ii) rapid digestion of sperm mtDNA just after fertilization. One notable point is that the digestion of mtDNA is achieved before the complete destruction of mitochondrial structures, which may be necessary to avoid the diffusion and transmission of potentially deleterious sperm mtDNA to the progeny. maternal inheritance ͉ medaka ͉ mtDNA M itochondria and chloroplasts contain their own genomes, which are believed to be vestiges of their bacterial ancestors (1). Mitochondrial (mt) and chloroplast (cp) genes are inherited in non-Mendelian fashion. A variety of patterns and mechanisms have been observed for the transmission of these genes, but in almost all eukaryotes, they are inherited mainly from the maternal parent (2-4).Generally, the maternal inheritance of mt (cp) DNA is thought to be a result of the dilution of the paternal contribution, because the paternal gametes (sperm) are much smaller than maternal gametes (egg) and contribute only a limited amount of cytoplasm to the progeny. In animals, a mature sperm carries Ϸ100 copies of mtDNA, which might be necessary to maintain the integrity of mitochondrial activity (5). In contrast, the animal oocyte contains Ϸ10 5 to 10 8 copies of mtDNA, exceeding that of sperm by a factor of at least 10 3 (3, 6). Therefore, the paternal contribution of mtDNA or cpDNA would be diluted beyond the limits of detection by using conventional restriction enzyme analysis (7).This simple explanation, however, has been challenged by many findings (8). For example, there have been several fairly unsuccessful attempts to detect leaky transmission of paternal mtDNA by repetitive backcross experiments using lepidopteran insects (9). On the contrary, in mussels (Mtylus), paternal mtDNA can be transmitted to male progeny at a remarkably high frequency, even though paternal mtDNAs are transmitted by sperm (10-12). A more striking example was found in the unicellular alga Chlamydomonas reinhardtii. In C. reinhardtii, despite the fact that mtϩ (female) and mtϪ (male) gametes contribute equal amounts of cytoplasm to the progeny, cpDNA is transmitted only from the mtϩ parent. One biochemical stud...

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“…2). Similar values have been reported for mt nucleoids in mosses, algae (2,17), and human cells (22,23), implying a structural similarity of mt nucleoids between these organisms.…”

Section: Discussionsupporting

confidence: 84%

“…In animals, however, studies on mt nucleoids are rare (22,23). Although the behaviors of sperm during fertilization have been extensively studied, mainly by transmission or scanning microscopy (24), these methods were not suitable for monitoring mtDNA or nucleoids.…”

mentioning

confidence: 99%

Active digestion of sperm mitochondrial DNA in single living sperm revealed by optical tweezers

Nishimura

Yoshinari

Naruse

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

144

104

View full text Add to dashboard Cite

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“…Outer membrane (OM)-targeted GFP and matrix-GFP showed similar dynamics in cell fusion experiments when complete fusion was observed [36]. By contrast, cell fusion and pa-GFP studies indicated that for inner membrane proteins (ABCB10; OXPHOS complexes), diffusion and exchange within a single mitochondrion were significantly slower than for mt-paGFP [60,61].…”

Section: The Measurement Of Mitochondrial Dynamics and Its Applicatiomentioning

confidence: 94%

“…It was also shown that mtDNA, such as matrix proteins, in principal, is exchanged between mitochondria [36]. Mitochondrial nucleoids can be visualized in assays by direct staining or using fluorescent mtDNA binding proteins (illustrated in figure 3a,b).…”

Section: The Measurement Of Mitochondrial Dynamics and Its Applicatiomentioning

confidence: 99%

Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity?

Busch

Kowald

Spelbrink

2014

Phil. Trans. R. Soc. B

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Mammalian mtDNA encodes for 13 core proteins of oxidative phosphorylation. Mitochondrial DNA mutations and deletions cause severe myopathies and neuromuscular diseases. Thus, the integrity of mtDNA is pivotal for cell survival and health of the organism. We here discuss the possible impact of mitochondrial fusion and fission on mtDNA maintenance as well as positive and negative selection processes. Our focus is centred on the important question of how the quality of mtDNA nucleoids can be assured when selection and mitochondrial quality control works on functional and physiological phenotypes constituted by oxidative phosphorylation proteins. The organelle control theory suggests a link between phenotype and nucleoid genotype. This is discussed in the light of new results presented here showing that mitochondrial transcription factor A/nucleoids are restricted in their intramitochondrial mobility and probably have a limited sphere of influence. Together with recent published work on mitochondrial and mtDNA heteroplasmy dynamics, these data suggest first, that single mitochondria might well be internally heterogeneous and second, that nucleoid genotypes might be linked to local phenotypes (although the link might often be leaky). We discuss how random or site-specific mitochondrial fission can isolate dysfunctional parts and enable their elimination by mitophagy, stressing the importance of fission in the process of mtDNA quality control. The role of fusion is more multifaceted and less understood in this context, but the mixing and equilibration of matrix content might be one of its important functions.

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“…Après fusion cellulaire, l'analyse du mélange des molécules fluorescentes entre mitochondries met en évidence la fusion mitochondriale ( Figure 2B, C). Ces études ont permis de démontrer que la fusion mitochondriale (1) permet l'échange de proté ines, de complexes respiratoires et de nucléo ïdes, (2) ne dépend pas du cytosquelette et (3) est abolie par une dissipation du potentiel de membrane mitochondrial (Δ m ) [5,6]. Elles ont également dévoilé que les membranes externe et interne fusionnent en deux réactions séparées et que seule la dernière est sensible à la dissipation du Δ m [7].…”

Section: Les Mitochondries Fusionnent Et Fissionnent Continuellementunclassified

Dynamique et morphologie mitochondriales

et al. 2010

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Les mitochondries, des organites de morphologie longtemps méconnueLes mitochondries ont été identifiées il y a plus de cent ans par microscopie photonique, mais on a longtemps ignoré leur véritable morphologie et leur nature dynamique. Le nom qui leur a alors été attribué, dérivé du grec mitos (fil) et chondros (grain), reflétait l'hétérogénéité de leur morphologie. La microscopie électronique révéla ensuite qu'elles sont entourées de deux membranes (externe et interne) et possèdent un troisième système membranaire : les crêtes de la membrane interne [1]. Ces clichés de microscopie électronique, dévoilant des structures punctiformes qui ressemblaient, en taille et en morphologie, à leurs ancêtres les bactéries, conduisent une partie de la communauté scientifique à considérer les mitochondries comme de petites entités indépendantes. Ce concept pose des questions fondamentales en termes de génétique mitochondriale. Les génomes mitochondriaux coexistent-ils dans un seul compartiment ou sont-ils isolés dans des centaines de mitochondries indépendantes ? Les mitochondries peuvent-elles réaliser des échanges moléculaires leur permettant de se complémenter ? La redécouverte et la caractérisation de la morphologie et de la dynamique mitochondriales permettront de répondre à ces interrogations. Le développement de nouvelles techniques de microscopie (microscopie électronique à tomographie, microscopie confocale) vers la fin du XX e siècle révéla à nouveau que les mitochondries peuvent adopter une structure punctiforme ou tubulaire. Dans les années 1990, des cribles génétiques menés chez la levure Saccharomyces cerevisiae ont conduit à l'isolement de mutants dont la morphologie des mitochondries était altérée et à l'identification des premières protéines impliquées dans la dynamique mitochondriale [2]. S. cerevisiae présente un réseau mitochondrial filamenteux qui résulte d'un équilibre dynamique entre deux forces antagonistes de fission et de fusion ( Figure 1A, B). Dans des conditions normales, l'équilibre fusion/ > Les mitochondries sont des organites dynamiques qui se déplacent, se divisent et fusionnent continuellement. L'équilibre fusion-fission détermine si elles forment, dans la cellule, des filaments interconnectés ou apparaissent comme une collection de structures ponctiformes indé-pendantes. Les machineries de fusion et fission sont conservées des levures aux mammifères et comprennent trois GTPases de la famille des dynamines : Dnm1/DRP1 (nomenclature levure/ homme pour dynamin-related protein), impliquée dans la fission, et Fzo1/MFN (mitofusine) et Mgm1/OPA1 (optic atrophy 1), requises pour la fusion. Alors que l'identification et la caractérisation des acteurs de la dynamique mitochondriale, de leur mécanisme d'action, de leurs fonctions et de leur régulation continuent à être l'objet de nombreuses recherches, la pertinence de ce processus est attestée par son rôle dans le fonctionnement mitochondrial, la survie cellulaire, le développement embryonnaire et son implication dans des maladies neurologiques. <

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Organization and dynamics of human mitochondrial DNA

Cited by 339 publications

References 42 publications

Active digestion of sperm mitochondrial DNA in single living sperm revealed by optical tweezers

Active digestion of sperm mitochondrial DNA in single living sperm revealed by optical tweezers

Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity?

Dynamique et morphologie mitochondriales

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