Mitochondrial morphology and distribution in mammalian cells

2006 ◽  
Vol 387 (12) ◽  
pp. 1551-1558 ◽  
Author(s):  
Ann E. Frazier ◽  
Clement Kiu ◽  
Diana Stojanovski ◽  
Nicholas J. Hoogenraad ◽  
Michael T. Ryan
Keyword(s):  
Cell Death ◽  
Neurological Disorders ◽  
Mammalian Cells ◽  
Morphological Changes ◽  
Mitochondrial Fission ◽  
Gene Mutations ◽  
Current Understanding ◽  
Mitochondrial Morphology ◽  
Cell Death Pathways ◽  
Mitochondrial Distribution

Abstract It is now appreciated that mitochondria form tubular networks that adapt to the requirements of the cell by undergoing changes in their shape through fission and fusion. Proper mitochondrial distribution also appears to be required for ATP delivery and calcium regulation, and, in some cases, for cell development. While we now realise the great importance of mitochondria for the cell, we are only beginning to work out how these organelles undergo the drastic morphological changes that are essential for cellular function. Of the few known components involved in shaping mitochondria, some have been found to be essential to life and their gene mutations are linked to neurological disorders, while others appear to be recruited in the activation of cell death pathways. Here we review our current understanding of the functions of the main players involved in mitochondrial fission, fusion and distribution in mammalian cells.

scholarly journals Mitochondrial fission process 1 (MTFP1) controls bioenergetic efficiency and prevents inflammatory cardiomyopathy and heart failure in mice

2021 ◽  
Author(s):  
Erminia Donnarumma ◽  
Michael Kohlhaas ◽  
Elodie Vimont ◽  
Etienne Kornobis ◽  
Thibaut Chaze ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Cell Death ◽  
Knockout Mice ◽  
Mitochondrial Permeability Transition ◽  
Mitochondrial Fission ◽  
Sterile Inflammation ◽  
Mitochondrial Morphology ◽  
Fission Process ◽  
General Decline

Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in adult-onset dilated cardiomyopathy (DCM) characterized by sterile inflammation and cardiac fibrosis that progressed to heart failure and middle-aged death. Failing hearts from cardiomyocyte-restricted knockout mice displayed a general decline in mitochondrial gene expression and oxidative phosphorylation (OXPHOS) activity. Pre-DCM, we observed no defects in mitochondrial morphology, content, gene expression, OXPHOS assembly nor phosphorylation dependent respiration. However, knockout cardiac mitochondria displayed reduced membrane potential and increased non-phosphorylation dependent respiration, which could be rescued by pharmacological inhibition of the adenine nucleotide translocase ANT. Primary cardiomyocytes from pre-symptomatic knockout mice exhibited normal excitation-contraction coupling but increased sensitivity to programmed cell death (PCD), which was accompanied by an opening of the mitochondrial permeability transition pore (mPTP). Intriguingly, mouse embryonic fibroblasts deleted for Mtfp1 recapitulated PCD sensitivity and mPTP opening, both of which could be rescued by pharmacological or genetic inhibition of the mPTP regulator Cyclophilin D. Collectively, our data demonstrate that contrary to previous in vitro studies, the loss of the MTFP1 promotes mitochondrial uncoupling and increases cell death sensitivity, causally mediating pathogenic cardiac remodeling.

scholarly journals An update on stem cell therapy for neurological disorders: cell death pathways as therapeutic targets

2017 ◽  
Vol 3 (1) ◽  
Author(s):  
Sydney Corey ◽  
Shaila Ghanekar ◽  
Jake Sokol ◽  
John H. Zhang ◽  
Cesar V. Borlongan
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Neurological Disorders ◽  
Therapeutic Targets ◽  
Cell Death Pathways

scholarly journals Mitochondrial morphology and activity regulate furrow ingression and contractile ring dynamics in Drosophila cellularization

2020 ◽  
Vol 31 (21) ◽  
pp. 2331-2347
Author(s):  
Sayali Chowdhary ◽  
Somya Madan ◽  
Darshika Tomer ◽  
Manos Mavrakis ◽  
Richa Rikhy
Keyword(s):  
Mitochondrial Fission ◽  
Cell Formation ◽  
Mitochondrial Morphology ◽  
Contractile Ring ◽  
Drosophila Embryogenesis ◽  
Ring Dynamics ◽  
Mitochondrial Distribution ◽  
Ring Constriction

Drp1-regulated mitochondrial fission is essential for mitochondrial distribution across the cell in cellularization during Drosophila embryogenesis. Loss of mitochondrial fission in Drp1 mutant embryos leads to defects in morphogenetic events of cell formation and contractile ring constriction in cellularization.

Mitochondrial dynamics in yeast cell death and aging

2011 ◽  
Vol 39 (5) ◽  
pp. 1520-1526 ◽  
Author(s):  
Ralf J. Braun ◽  
Benedikt Westermann
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Mitochondrial Dynamics ◽  
Progressive Increase ◽  
Mitochondrial Morphology ◽  
Aging Research ◽  
Yeast Saccharomyces Cerevisiae ◽  
Cell Death Pathways ◽  
Dependent Cell ◽  
Mitochondrial Networks

Mitochondria play crucial roles in programmed cell death and aging. Different stimuli activate distinct mitochondrion-dependent cell death pathways, and aging is associated with a progressive increase in mitochondrial damage, culminating in oxidative stress and cellular dysfunction. Mitochondria are highly dynamic organelles that constantly fuse and divide, forming either interconnected mitochondrial networks or separated fragmented mitochondria. These processes are believed to provide a mitochondrial quality control system and enable an effective adaptation of the mitochondrial compartment to the metabolic needs of the cell. The baker's yeast, Saccharomyces cerevisiae, is an established model for programmed cell death and aging research. The present review summarizes how mitochondrial morphology is altered on induction of cell death or on aging and how this correlates with the induction of different cell death pathways in yeast. We highlight the roles of the components of the mitochondrial fusion and fission machinery that affect and regulate cell death and aging.

scholarly journals Fzo1, a Protein Involved in Mitochondrial Fusion, Inhibits Apoptosis

2004 ◽  
Vol 279 (50) ◽  
pp. 52726-52734 ◽  
Author(s):  
Rie Sugioka ◽  
Shigeomi Shimizu ◽  
Yoshihide Tsujimoto
Keyword(s):  
Cell Death ◽  
Conformational Changes ◽  
Apoptotic Cell ◽  
Mitochondrial Fission ◽  
Apoptotic Cell Death ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Human Homolog ◽  
Mitochondrial Fragmentation ◽  
Apoptotic Death

Mitochondrial morphology and physiology are regulated by the processes of fusion and fission. Some forms of apoptosis are reported to be associated with mitochondrial fragmentation. We showed that overexpression of Fzo1A/B (rat) proteins involved in mitochondrial fusion, or silencing of Dnm1 (rat)/Drp1 (human) (a mitochondrial fission protein), increased elongated mitochondria in healthy cells. After apoptotic stimulation, these interventions inhibited mitochondrial fragmentation and cell death, suggesting that a process involved in mitochondrial fusion/fission might play a role in the regulation of apoptosis. Consistently, silencing of Fzo1A/B or Mfn1/2 (a human homolog of Fzo1A/B) led to an increase of shorter mitochondria and enhanced apoptotic death. Overexpression of Fzo1 inhibited cytochromecrelease and activation of Bax/Bak, as assessed from conformational changes and oligomerization. Silencing of Mfn or Drp1 caused an increase or decrease of mitochondrial sensitivity to apoptotic stimulation, respectively. These results indicate that some of the proteins involved in mitochondrial fusion/fission modulate apoptotic cell death at the mitochondrial level.

scholarly journals Roles of the Mammalian Mitochondrial Fission and Fusion Mediators Fis1, Drp1, and Opa1 in Apoptosis

2004 ◽  
Vol 15 (11) ◽  
pp. 5001-5011 ◽  
Author(s):  
Yang-ja Lee ◽  
Seon-Yong Jeong ◽  
Mariusz Karbowski ◽  
Carolyn L. Smith ◽  
Richard J. Youle
Keyword(s):  
Mammalian Cells ◽  
Mitochondrial Fission ◽  
Mitochondrial Morphology ◽  
Apoptosis Induction ◽  
Wild Type ◽  
Mitochondrial Fragmentation ◽  
Down Regulation ◽  
Multiple Components ◽  
Mitochondrial Morphogenesis ◽  
Short Hairpin Rnas

During apoptosis, the mitochondrial network fragments. Using short hairpin RNAs for RNA interference, we manipulated the expression levels of the proteins hFis1, Drp1, and Opa1 that are involved in mitochondrial fission and fusion in mammalian cells, and we characterized their functions in mitochondrial morphology and apoptosis. Down-regulation of hFis1 powerfully inhibits cell death to an extent significantly greater than down-regulation of Drp1 and at a stage of apoptosis distinct from that induced by Drp1 inhibition. Cells depleted of Opa1 are extremely sensitive to exogenous apoptosis induction, and some die spontaneously by a process that requires hFis1 expression. Wild-type Opa1 may function normally as an antiapoptotic protein, keeping spontaneous apoptosis in check. However, if hFis1 is down-regulated, cells do not require Opa1 to prevent apoptosis, suggesting that Opa1 may be normally counteracting the proapoptotic action of hFis1. We also demonstrate in this study that mitochondrial fragmentation per se does not result in apoptosis. However, we provide further evidence that multiple components of the mitochondrial morphogenesis machinery can positively and negatively regulate apoptosis.

scholarly journals Mitochondrial dynamics and mitophagy are necessary for proper invasive growth in Rice Blast

2019 ◽  
Author(s):  
Yanjun Kou ◽  
Yunlong He ◽  
Jiehua Qiu ◽  
Shu Yazhou ◽  
Fan Yang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Blast Disease ◽  
Cereal Crops ◽  
Mitochondrial Morphology ◽  
Invasive Growth ◽  
In Planta ◽  
Antioxidant Treatment

SUMMARYMagnaporthe oryzaecauses Blast disease, which is one of the most devastating infections in rice and several important cereal crops.M. oryzaeneeds to coordinate gene regulation, morphological changes, nutrient acquisition, and host evasion, in order to invade and proliferate within the plant tissues. Thus far, the molecular mechanisms underlying the regulation of invasive growthin plantahave remained largely unknown. We identified a precise filamentous-punctate-filamentous cycle in mitochondrial morphology duringMagnaporthe-Rice interaction. Interestingly, loss of either the mitochondrial fusion (MoFzo1) or fission (MoDnm1) machinery, or inhibition of mitochondrial fission using Mdivi-1 caused significant reduction inM. oryzaepathogenicity. Furthermore, exogenous carbon source(s) but not antioxidant treatment delayed such mitochondrial dynamics/transition during invasive growth. Such nutrient-based regulation of organellar dynamics preceded MoAtg24-mediated mitophagy, which was found to be essential for proper biotrophic development and invasive growthin planta. We propose that precise mitochondrial dynamics and mitophagy occur during the transition from biotrophy to necrotrophy, and are required for proper induction and establishment of the blast disease in rice.

scholarly journals Depletion of a Toxoplasma porin leads to defects in mitochondrial morphology and contacts with the ER

2021 ◽  
Author(s):  
Natalia Mallo ◽  
Jana Ovciarikova ◽  
Erica S. Martins-Duarte ◽  
Stephan C. Baehr ◽  
Marco Biddau ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Protein Import ◽  
Morphological Changes ◽  
Anion Channel ◽  
Multiple Roles ◽  
Mitochondrial Morphology ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent ◽  
Molecule Transport ◽  
Small Molecule Transport

The Voltage Dependent Anion channel (VDAC) is a ubiquitous channel in the outer membrane of the mitochondrion with multiple roles in protein, metabolite and small molecule transport. In mammalian cells, VDAC, as part of a larger complex including the inositol triphosphate receptor, has been shown to have a role in mediating contacts between the mitochondria and endoplasmic reticulum (ER). We identify VDAC of the pathogenic apicomplexan Toxoplasma gondii and demonstrate its importance for parasite growth. We show that VDAC is involved in protein import and metabolite transfer to mitochondria. Further, depletion of VDAC resulted in significant morphological changes of the mitochondrion and ER, suggesting a role in mediating contacts between these organelles in T. gondii.

Abstract 393: MCL-1 Promotes Survival and Influences Mitochondrial Dynamics in Cardiac Myocytes

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Alexandra G Moyzis ◽  
Robert L Thomas ◽  
Jennifer Kuo ◽  
Åsa B Gustafsson
Keyword(s):  
Cell Death ◽  
Cardiac Myocytes ◽  
Apoptotic Cell ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Apoptotic Cell Death ◽  
Mitochondrial Fusion ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Morphology ◽  
Rapid Degradation

The BCL-2 family proteins are important regulators of mitochondrial structure and integrity. MCL-1 is an anti-apoptotic BCL-2 protein that is highly expressed in the myocardium compared to the other anti-apoptotic proteins BCL-2 and BCL-X L. Recently, we reported that MCL-1 is essential for myocardial homeostasis. Cardiac-specific deletion of MCL-1 in mice led to rapid mitochondrial dysfunction, hypertrophy, and lethal cardiomyopathy. Surprisingly, MCL-1 deficient myocytes did not undergo apoptotic cell death. Instead, the cells displayed signs of mitochondrial deterioration and necrotic cell death, suggesting that MCL-1 has an additional role in maintaining mitochondrial function in cardiac myocytes. Similarly, deletion of MCL-1 in fibroblasts caused rapid mitochondrial fragmentation followed by cell death at 72 hours. Interestingly, the MCL-1 deficient fibroblasts retained cytochrome c in the mitochondria , confirming that the cells were not undergoing apoptotic cell death. We have also identified that MCL-1 localizes to the mitochondrial outer membrane (OM) and the matrix in the myocardium and that the two forms respond differently to stress. MCL-1 OM was rapidly degraded after myocardial infarction or fasting, whereas MCL-1 Matrix levels were maintained. Similarly, starvation of MEFs resulted in rapid degradation of MCL-1 OM , whereas MCL-1 Matrix showed delayed degradation. Treatment with the mitochondrial uncoupler FCCP led to rapid degradation of both forms. This suggests that the susceptibility to degradation is dependent on its localization and the nature of the stress. Our data also suggests that these two forms perform distinct functions in regulating mitochondrial morphology and survival. Overexpression of MCL-1 Matrix promoted mitochondrial fusion in fibroblasts under baseline conditions and protected cells against FCCP-mediated mitochondrial fission and clearance by autophagosomes. Thus, our data suggest that MCL-1 exists in two separate locations where it performs different functions. MCL-1 Matrix promotes mitochondrial fusion, which protects cells against excessive mitochondrial clearance during unfavorable conditions.

Abstract 14: Pim-1 Preserves Mitochondrial Morphology by Inhibiting Drp1 Translocation

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Shabana Din ◽  
Matt Mason ◽  
Mirko Volkers ◽  
Bevan Johnson ◽  
Mathias Konstandin ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Morphological Changes ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Dominant Negative ◽  
Neonatal Rat ◽  
Mitochondrial Morphology ◽  
Mitochondrial Fragmentation ◽  
Simulated Ischemia

Rationale: Mitochondrial morphological dynamics affect the outcome of ischemic heart damage. Mitochondrial fission protein Dynamin Related Protein 1 (Drp1) is a mediator of mitochondrial morphological changes and cell death during ischemic injury. Mitochondrial integrity is maintained by cardioprotective kinase Pim1, which enhances resistance to apoptotic challenge and ischemia reperfusion injury. In this study we examine the relationship between Pim1 activity and Drp1 regulation of mitochondrial morphology in cardiomyocytes challenged by ischemia. Objective: To demonstrate that Pim1 inhibits Drp1 translocation to the mitochondria in response to ischemic injury. Methods and Results: Simulated ischemia and simulated ischemia reperfusion (sI & sI/R) induced mitochondrial fragmentation and cell death in neonatal rat cardiac myocytes (NRCM), respectively. Mitochondrial fragmentation accompanied Drp1 translocation to the mitochondria in NRCM. Inhibition of Drp1 by mdivi1 preserved mitochondrial reticular morphology and inhibited apoptotic cell death. Mice subjected to sI/R injury displayed Drp1 mitochondrial localization, while exposure to mdivi1 led to reduced infarct size. Interestingly, transgenic hearts overexpressing Pim1 decreased total Drp1 levels, increased phosphorylation of Drp1 at serine 637, and inhibited Drp1 localization to mitochondria while preserving reticular morphology after sI. In contrast, Pim1 dominant negative (PDN) transgenic hearts and NRCM exhibit increased Drp1 translocation to mitochondria and fragmented mitochondria. PDN hearts exhibit decreased phosphorylation of serine 637 and upregulation of BH3 protein PUMA, inducing Drp1 accumulation at mitochondria and increased sensitivity to apoptotic stimuli. In PDN NRCMs, overexpression of Puma dominant negative (PumaDN) attenuated localization of Drp1 to mitochondria and inhibited cell death during sI. Conclusion: Pim1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology in response to simulated ischemia. Therefore, selective manipulation of Pim1 should be pursued as a therapeutic target to maintain mitochondrial morphology for cardioprotection.

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