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Mitochondrial dynamics generate equal distribution but patchwork localization of respiratory Complex I.

Highly dynamic mitochondrial morphology is a prerequisite for fusion and fission. Mitochondrial fusion may represent a rescue mechanism for impaired mitochondria by exchanging constituents (proteins, lipids and mitochondrial DNA) and thus maintaining functionality. Here we followed for the first time the dynamics of a protein complex of the respiratory chain during fusion and fission. HeLa cells with differently labelled respiratory Complex I were fused and the dynamics of Complex I were investigated. The mitochondrial proteins spread throughout the whole mitochondrial population within 3 to 6 h after induction of cell fusion. Mitochondria of fused cells displayed a patchy substructure where the differently labelled proteins occupied separate and distinct spaces. This patchy appearance was already--although less pronounced--observed within single mitochondria before fusion, indicating a specific localization of Complex I with restricted diffusion within the inner membrane. These findings substantiate the view of a homogenous mitochondrial population due to constantly rearranging mitochondria, but also indicate the existence of distinct inner mitochondrial sub-compartments for respiratory chain complexes.

Animals↗
PubMed2006

Mitochondrial dynamics and aging: Mitochondrial interaction preventing individuals from expression of respiratory deficiency caused by mutant mtDNA.

In mammalian cells, there is an extensive and continuous exchange of mitochondrial DNA (mtDNA) and its products between mitochondria. This mitochondrial complementation prevents individuals from expression of respiration deficiency caused by mutant mtDNAs. Thus, the presence of mitochondrial complementation does not support the generally accepted mitochondrial theory of aging, which proposes that accumulation of somatic mutations in mtDNA is responsible for age-associated mitochondrial dysfunction. Moreover, the presence of mitochondrial complementation enables gene therapy for mitochondrial diseases using nuclear transplantation of zygotes.

Aging↗
PubMed1998

Mitochondrial dynamics in yeast.

Proteins that control mitochondrial dynamics in yeast are being identified at a rapid pace. These proteins include cytoskeletal elements that regulate organelle distribution and inheritance and several outer membrane proteins that are required to maintain the branched, mitochondrial reticulum. Interestingly, three of the high molecular weight GTPases encoded by the yeast genome are required for mitochondrial integrity and are potential regulators of mitochondrial branching, distribution, and membrane fusion. The recent finding that mtDNA mixing is restricted in the mitochondrial matrix has stimulated the hunt for the molecular machinery that anchors mitochondrial nucleoids in the organelle. Considering that many aspects of mitochondrial structure and behavior are strikingly similar in different cell types, the functional analyses of these yeast proteins should provide general insights into the mechanisms governing mitochondrial dynamics in all eukaryotes.

Cell Cycle↗
PubMed2004

Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis.

A dynamic balance of organelle fusion and fission regulates mitochondrial morphology. During apoptosis this balance is altered, leading to an extensive fragmentation of the mitochondria. Here, we describe a novel assay of mitochondrial dynamics based on confocal imaging of cells expressing a mitochondrial matrix-targeted photoactivable green fluorescent protein that enables detection and quantification of organelle fusion in living cells. Using this assay, we visualize and quantitate mitochondrial fusion rates in healthy and apoptotic cells. During apoptosis, mitochondrial fusion is blocked independently of caspase activation. 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.

Amino Acid Chloromethyl Ketones↗
PubMed2006

A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics.

In this study, we have identified a novel mitochondrial ubiquitin ligase, designated MITOL, which is localized in the mitochondrial outer membrane. MITOL possesses a Plant Homeo-Domain (PHD) motif responsible for E3 ubiquitin ligase activity and predicted four-transmembrane domains. MITOL displayed a rapid degradation by autoubiquitination activity in a PHD-dependent manner. HeLa cells stably expressing a MITOL mutant lacking ubiquitin ligase activity or MITOL-deficient cells by small interfering RNA showed an aberrant mitochondrial morphology such as fragmentation, suggesting the enhancement of mitochondrial fission by MITOL dysfunction. Indeed, a dominant-negative expression of Drp1 mutant blocked mitochondrial fragmentation induced by MITOL depletion. We found that MITOL associated with and ubiquitinated mitochondrial fission protein hFis1 and Drp1. Pulse-chase experiment showed that MITOL overexpression increased turnover of these fission proteins. In addition, overexpression phenotype of hFis1 could be reverted by MITOL co-overexpression. Our finding indicates that MITOL plays a critical role in mitochondrial dynamics through the control of mitochondrial fission proteins.

Amino Acid Sequence↗
PubMed2006

Critical dependence of neurons on mitochondrial dynamics.

The selective disruption of certain cell types--notably neurons--in diseases involving mitochondrial dysfunction is thought to reflect the high-energy requirements of these cells, but few details are known. Recent studies have provided clues to the cellular basis of this mitochondrial requirement. Mitochondria are regionally organized within some nerve cells, with higher accumulations in the soma, the hillock, the nodes of Ranvier and the nerve terminal. In the synaptic region, mitochondria regulate calcium and ATP levels, thereby maintaining synaptic transmission and structure. Defects in mitochondrial dynamics can cause deficits in mitochondrial respiration, morphology and motility. Moreover, mutations in the mitochondrial fusion genes Mitofusin-2 and OPA1 lead to the peripheral neuropathy Charcot-Marie-Tooth type 2A and dominant optic atrophy. 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.

Animals↗
PubMed2005

Mitochondrial Dynamics in Cell Life and Death.

Mitochondria are dynamic organelles that are able to change their morphology during cellular development and to meet the energetic needs of the cell, for example. During the past several years, knowledge about the molecular machinery involved in the control of mitochondrial shape has improved considerably. In August 2005, leading researchers in the field of mitochondrial dynamics met at the Venetian Institute of Molecular Medicine in Padova, Italy, to discuss novel and intriguing findings presented at the first workshop on "Mitochondrial Dynamics in Cell Life and Death." Some of the findings related to apoptosis and aging are described in this Perspective.

Aging↗
PubMed2006

Mitochondrial dynamics and disease, OPA1.

The mitochondria are dynamic organelles that constantly fuse and divide. An equilibrium between fusion and fission controls the morphology of the mitochondria, which appear as dots or elongated tubules depending the prevailing force. Characterization of the components of the fission and fusion machineries has progressed considerably, and the emerging question now is what role mitochondrial dynamics play in mitochondrial and cellular functions. Its importance has been highlighted by the discovery that two human diseases are caused by mutations in the two mitochondrial pro-fusion genes, MFN2 and OPA1. This review will focus on data concerning the function of OPA1, mutations in which cause optic atrophy, with respect to the underlying pathophysiological processes.

GTP Phosphohydrolases↗
PubMed2006

Normal mitochondrial dynamics requires rhomboid-7 and affects Drosophila lifespan and neuronal function.

In addition to being energy generators, mitochondria control many cellular processes including apoptosis. They are dynamic organelles, and the machinery of membrane fusion and fission is emerging as a key regulator of mitochondrial biology. We have recently identified a novel and conserved mitochondrial rhomboid intramembrane protease that controls membrane fusion in Saccharomyces cerevisiae by processing the dynamin-like GTPase, Mgm1, thereby releasing it from the membrane. The genetics of mitochondrial membrane dynamics has until now focused primarily on yeast. Here we show that in Drosophila, the mitochondrial rhomboid (Rhomboid-7) is required for mitochondrial fusion during fly spermatogenesis and muscle maturation, both tissues with unusual mitochondrial dynamics. We also find that mutations in Drosophila optic atrophy 1-like (Opa1-like), the ortholog of yeast mgm1, display similar phenotypes, suggesting a shared role for Rhomboid-7 and Opa1-like, as with their yeast orthologs. Loss of human OPA1 leads to dominant optic atrophy, a mitochondrial disease leading to childhood onset blindness. rhomboid-7 mutant flies have severe neurological defects, evidenced by compromised signaling across the first visual synapse, as well as light-induced neurodegeneration of photoreceptors that resembles the human disease. rhomboid-7 mutant flies also have a greatly reduced lifespan.

Animals↗
PubMed2006

Plant mitochondrial dynamics.

Higher plant mitochondria are dynamic, pleomorphic organelles. The higher plant chondriome (all mitochondria in a cell collectively) is typically composed of numerous, physically discrete, mitochondria. However, frequent inter-mitochondrial fusion, enabling the mixing and recombination of mtDNA, ensures that the higher plant chondriome functions, at least genetically, as a discontinuous whole. Nothing is known about the genes controlling mitochondrial fusion in plants; there are no plant homologues of most of the genes known to be involved in fusion in other organisms. In contrast, the mitochondrial fission apparatus is generally conserved. Higher plant mitochondria use dynamin-like and Fis-type proteins for division; like yeast and animals, higher plants have lost the mitochondrial-specific form of the prokaryote-derived protein, FtsZ. In addition to being providers of energy for life, mitochondria provide a trigger for death. The role of mitochondrial dynamics in the initiation and promulgation of cell death is conserved in higher plants although there are specific differences in the genes and mechanisms involved relative to other higher eukaryotes.

Biological Evolution↗
PubMed2000

Yeast mitochondrial dynamics: fusion, division, segregation, and shape.

Mitochondria are essential organelles found in virtually all eukaryotic cells that play key roles in a variety of cellular processes. Mitochondria show a striking heterogeneity in their number, location, and shape in many different cell types. Although the dynamic nature of mitochondria has been known for decades, the molecules and mechanisms that mediate these processes are largely unknown. Recently, several laboratories have isolated and analyzed mutants in the yeast Saccharomyces cerevisiae defective in mitochondrial fusion and division, in the segregation of mitochondria to daughter cells, and in the establishment and maintenance of mitochondrial shape. These studies have identified several proteins that appear to mediate different aspects of mitochondrial morphogenesis. Although it is clear that many additional components have yet to be identified, some of the newly discovered proteins raise intriguing possibilities for how the processes of mitochondrial division, fusion, and segregation occur. Below we summarize our current understanding of the molecules known to be required for yeast mitochondrial dynamics.

Cell Division↗
PubMed2006

Orchestration of lymphocyte chemotaxis by mitochondrial dynamics.

Lymphocyte traffic is required to maintain homeostasis and perform appropriate immunological reactions. To migrate into inflamed tissues, lymphocytes must acquire spatial and functional asymmetries. Mitochondria are highly dynamic organelles that distribute in the cytoplasm to meet specific cellular needs, but whether this is essential to lymphocyte functions is unknown. We show that mitochondria specifically concentrate at the uropod during lymphocyte migration by a process involving rearrangements of their shape. Mitochondrial fission facilitates relocation of the organelles and promotes lymphocyte chemotaxis, whereas mitochondrial fusion inhibits both processes. Our data substantiate a new role for mitochondrial dynamics and suggest that mitochondria redistribution is required to regulate the motor of migrating cells.

Adenosine Triphosphate↗
PubMed2002

Rab32 is an A-kinase anchoring protein and participates in mitochondrial dynamics.

A-kinase anchoring proteins (AKAPs) tether the cAMP-dependent protein kinase (PKA) and other signaling enzymes to distinct subcellular organelles. Using the yeast two-hybrid approach, we demonstrate that Rab32, a member of the Ras superfamily of small molecular weight G-proteins, interacts directly with the type II regulatory subunit of PKA. Cellular and biochemical studies confirm that Rab32 functions as an AKAP inside cells. Anchoring determinants for PKA have been mapped to sites within the conserved alpha5 helix that is common to all Rab family members. Subcellular fractionation and immunofluorescent approaches indicate that Rab32 and a proportion of the cellular PKA pool are associated with mitochondria. Transient transfection of a GTP binding-deficient mutant of Rab32 promotes aberrant accumulation of mitochondria at the microtubule organizing center. Further analysis of this mutant indicates that disruption of the microtubule cytoskeleton results in aberrantly elongated mitochondria. This implicates Rab32 as a participant in synchronization of mitochondrial fission. Thus, Rab32 is a dual function protein that participates in both mitochondrial anchoring of PKA and mitochondrial dynamics.

Amino Acid Sequence↗
PubMed2026

Functional impact of Nth like DNA glycosylase 1 on mitochondrial dynamics.

Nth like DNA glycosylase 1 (NTHL1), a key base excision repair enzyme, has long been considered essential for nuclear and mitochondrial genome integrity. Combining in vitro biochemical assays, in cellulo molecular biology, and bioinformatic analyses, we investigated how NTHL1 loss affects mitochondrial DNA (mtDNA) stability and mitochondrial function. Contrary to the conventional view that mtDNA damage is solely detrimental, we find that NTHL1 loss confers a beneficial, mitochondria-initiated phenotype in human cells. Despite accumulating mtDNA lesions, NTHL1 loss unexpectedly increases mtDNA copy number, elevates oxidative phosphorylation protein levels, and enhances mitochondrial respiration. NTHL1-/- cells also show increased mitochondrial mass and higher levels of the biogenesis regulator PGC1α and the fusion protein OPA1, indicating an adaptive response that boosts mitochondrial function and capacity. Consequently, NTHL1-/- cells exhibit resistance to mitochondrial stress, accompanied by increased eIF2α phosphorylation and reduced MYC levels, converging on a broader transcriptional adaptive program. This phenotype depends on mitochondrial NTHL1 and reactive oxygen species (ROS) signaling, since treatment with ROS scavengers or mitochondria-specific reintroduction of NTHL1 rescues it. Together, these findings position NTHL1 as a key modulator of mtDNA stability and mitochondrial function, revealing that loss of this DNA repair enzyme shifts cellular metabolism toward a stress-adaptive state and enhances resilience to oxidative stress.

Humans↗
PubMed2002

Mitochondrial dynamics and division in budding yeast.

Mitochondria adopt a variety of different shapes in eukaryotic cells, ranging from multiple, small compartments to elaborate tubular networks. The establishment and maintenance of different mitochondrial morphologies depends, in part, on the equilibrium between opposing fission and fusion events. Recent studies in yeast, flies, worms and mammalian cells indicate that three high-molecular-weight GTPases control mitochondrial membrane dynamics. One of these is a dynamin-related GTPase that acts on the outer mitochondrial membrane to regulate fission. Recently, genetic approaches in budding yeast have identified additional components of the fission machinery. These and other new findings suggest a common mechanism for membrane fission events that has been conserved and adapted during eukaryotic evolution.

Cell Cycle↗
PubMed2004

Importance of mitochondrial dynamics during meiosis and sporulation.

Opposing fission and fusion events maintain the yeast mitochondrial network. Six proteins regulate these membrane dynamics during mitotic growth-Dnm1p, Mdv1p, and Fis1p mediate fission; Fzo1p, Mgm1p, and Ugo1p mediate fusion. Previous studies established that mitochondria fragment and rejoin at distinct stages during meiosis and sporulation, suggesting that mitochondrial fission and fusion are required during this process. Here we report that strains defective for mitochondrial fission alone, or both fission and fusion, complete meiosis and sporulation. However, visualization of mitochondria in sporulating cultures reveals morphological defects associated with the loss of fusion and/or fission proteins. Specifically, mitochondria collapse to one side of the cell and fail to fragment during presporulation. In addition, mitochondria are not inherited equally by newly formed spores, and mitochondrial DNA nucleoid segregation defects give rise to spores lacking nucleoids. This nucleoid inheritance defect is correlated with an increase in petite spore colonies. Unexpectedly, mitochondria fragment in mature tetrads lacking fission proteins. The latter finding suggests either that novel fission machinery operates during sporulation or that mechanical forces generate the mitochondrial fragments observed in mature spores. These results provide evidence of fitness defects caused by fission mutations and reveal new phenotypes associated with fission and fusion mutations.

Cell Respiration↗