Loss of Drp1 function alters OPA1 processing and changes mitochondrial membrane organization

Möpert, Kristin; Hájek, Petr; Frank, Stephan; Chen, Christiane; Kaufmann, Jörg; Santel, Ansgar

doi:10.1016/j.yexcr.2009.04.016

Cited by 62 publications

(59 citation statements)

References 46 publications

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“…Although additional studies are necessary to fully understand how PINK1 overexpression forms these donut-shaped mitochondria, our data indicate enhanced fusion or inhibition of fission is a possible mechanism. Similar mitochondrial morphology has also been shown in HeLa cells overexpressing parkin and Drp1 K38A (38), Mfn2 (39), and siRNA-Drp1 (40). Additionally, when van der Bliek and co-workers (36) expressed different dominant negative mutations of Drp1 in COS7 cells, they demonstrated that mitochondrial phenotypes range from highly interconnected to collapsed and fragmented networks under gradient conditions ranging from weak to strong fission inhibition.…”

Section: Discussionsupporting

confidence: 61%

Perturbations in Mitochondrial Dynamics Induced by Human Mutant PINK1 Can Be Rescued by the Mitochondrial Division Inhibitor mdivi-1

Cui

Tang

Christian

et al. 2010

Journal of Biological Chemistry

178

155

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Mutations in the mitochondrial encoded protein PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive Parkinson disease (PD). In mammalian cells, mutant PINK1 has been reported to promote fission or inhibit fusion in mitochondria; however, the mechanism by which this process occurs remains elusive. Using an ecdysone-inducible expression system in mammalian dopaminergic neuronal cells, we report here that human mutant PINK1 (L347P and W437X) mediates an overall fission effect by increasing the ratio of mitochondrial fission over fusion proteins, leading to excessive dysfunctional fragmented mitochondria. Knocking down endogenous Pink1 produces similar effects. In contrast, overexpressing human wild type PINK1 produces a pro-fusion effect by increasing the ratio of mitochondrial fusion/fission proteins without resulting in functionally compromised mitochondria. Parkin knockdown blocks the imbalance in fission/fusion proteins. Furthermore, overexpressing parkin and ubiquitin increases degradation of the mitochondrial fission hFis1 protein, suggesting PINK1 and parkin maintain proper mitochondrial function and integrity via the fission/fusion machinery. Through genetic manipulations and treatment with the small molecule mitochondrial division inhibitor (mdivi-1), which inhibits DLP1/Drp1, both structural and functional mitochondrial defects induced by mutant PINK1 were attenuated, highlighting a potential novel therapeutic avenue for Parkinson disease.The discoveries of mutations in the mitochondrial protein PTEN-induced putative kinase 1 (PINK1) 2 as a cause of autosomal recessive PD (1-3) have fueled the longstanding interest in the role of mitochondrial dysfunction in PD. Currently about 50 PINK1 mutations have been reported (4), making it the second most common causative gene for autosomal recessive PD after parkin, an E3 ubiquitin ligase that has been shown to function downstream of PINK1 and to affect mitochondrial morphology (5-8). Although PINK1 mutations are spread throughout the gene, they are most commonly found in the region encoding the functional serine/threonine kinase domain at the C terminus, leading to loss of PINK1 kinase activity. Recently this kinase domain has been shown to face the cytoplasm (9), providing evidence of spatial proximity to allow this mitochondrial protein to directly interact with cytosolic parkin.Current consensus is that PINK1 is a protective protein. Supporting this role, PINK1 overexpression confers resistance to staurosporine, MPP ϩ , and rotenone toxicity in cultured cells (10, 11) as well as to MPTP-induced dopaminergic neuronal loss in mice (12). Conversely, reducing PINK1 levels by RNAi in cultured cells leads to enhanced cell death in the presence of MPP ϩ and rotenone (12, 13). Mitochondrial defects leading to degeneration of flight muscles and loss of dopaminergic neurons have also been reported in Pink1-deficient Drosophila (5, 14). In recent years, PINK1 has gained significant attention for its role in mitochondrial dynamics (fission, fusion, and migrati...

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Section: Discussionsupporting

confidence: 61%

Perturbations in Mitochondrial Dynamics Induced by Human Mutant PINK1 Can Be Rescued by the Mitochondrial Division Inhibitor mdivi-1

Cui

Tang

Christian

et al. 2010

Journal of Biological Chemistry

178

155

View full text Add to dashboard Cite

show abstract

“…1B it can be seen that Higd-1a depletion affects the ratio of L and S forms of Opa1 as does silencing of Drp1. Möpert et al reported that persistent loss of Drp1 led to processing of Opa1 to shorter forms (24). We therefore examined the levels of fusion-and fission-related proteins in Higd-1a-depleted cells.…”

Section: Resultsmentioning

confidence: 97%

“…We found that silencing of Higd-1a in HeLa cells resulted in highly fragmented mitochondria in 89.3 ± 3.5% of the cells examined; the mitochondria resembled the dot-like fragmented mitochondria seen in cells transfected with Opa1 siRNA (96.1 ± 2.3%) or Mfn1 siRNA (81.5 ± 4.3%). It was shown that when HeLa cells were transfected with both Drp1 siRNA and Opa1 siRNA, the mitochondria lost their elongated shape (24). This result suggested that optimal expression of Opa1 was required to generate the fused and interconnected shape of mitochondria.…”

Section: Resultsmentioning

confidence: 99%

Higd-1a interacts with Opa1 and is required for the morphological and functional integrity of mitochondria

Cho

Lee

et al. 2013

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

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The activity and morphology of mitochondria are maintained by dynamic fusion and fission processes regulated by a group of proteins residing in, or attached to, their inner and outer membranes. Hypoxia-induced gene domain protein-1a (Higd-1a)/HIMP1-a/HIG1, a mitochondrial inner membrane protein, plays a role in cell survival under hypoxic conditions. In the present study, we showed that Higd-1a depletion resulted in mitochondrial fission, depletion of mtDNA, disorganization of cristae, and growth retardation. We demonstrated that Higd-1a functions by specifically binding to Optic atrophy 1 (Opa1), a key element in fusion of the inner membrane. In the absence of Higd-1a, Opa1 was cleaved, resulting in the loss of its long isoforms and accumulation of small soluble forms. The small forms of Opa1 do not interact with Higd-1a, suggesting that a part of Opa1 in or proximal to the membrane is required for that interaction. Opa1 cleavage, mitochondrial fission, and cell death induced by dissipation of the mitochondrial membrane potential were significantly inhibited by ectopic expression of Higd-1a. Furthermore, growth inhibition due to Higd-1a depletion could be overcome by overexpression of a noncleavable form of Opa1. Collectively, our observations demonstrate that Higd-1a inhibits Opa1 cleavage and is required for mitochondrial fusion by virtue of its interaction with Opa1.

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“…OPA1 may mediate ectopic fusion between inner and outer membranes closely contacted by matrix bulging, forming a transient lipid channel for matrix leak (96). Interestingly, increased proteolytic cleavage of OPA1 was observed in DLP1-null cells as well as with DLP1 silencing (96,116). The cleavage of l-OPA1 to s-OPA1 occurs with a loss of membrane potential.…”

Section: Figmentioning

confidence: 99%

Mitochondrial Dynamics in Diabetic Cardiomyopathy

Galloway

Yoon

2015

Antioxidants & Redox Signaling

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Significance: Cardiac function is energetically demanding, reliant on efficient well-coupled mitochondria to generate adenosine triphosphate and fulfill the cardiac demand. Predictably then, mitochondrial dysfunction is associated with cardiac pathologies, often related to metabolic disease, most commonly diabetes. Diabetic cardiomyopathy (DCM), characterized by decreased left ventricular function, arises independently of coronary artery disease and atherosclerosis. Dysregulation of Ca 2+ handling, metabolic changes, and oxidative stress are observed in DCM, abnormalities reflected in alterations in mitochondrial energetics. Cardiac tissue from DCM patients also presents with altered mitochondrial morphology, suggesting a possible role of mitochondrial dynamics in its pathological progression. Recent Advances: Abnormal mitochondrial morphology is associated with pathologies across diverse tissues, suggesting that this highly regulated process is essential for proper cell maintenance and physiological homeostasis. Highly structured cardiac myofibers were hypothesized to limit alterations in mitochondrial morphology; however, recent work has identified morphological changes in cardiac tissue, specifically in DCM. Critical Issues: Mitochondrial dysfunction has been reported independently from observations of altered mitochondrial morphology in DCM. The temporal relationship and causative nature between functional and morphological changes of mitochondria in the establishment/progression of DCM is unclear. Future Directions: Altered mitochondrial energetics and morphology are not only causal for but also consequential to reactive oxygen species production, hence exacerbating oxidative damage through reciprocal amplification, which is integral to the progression of DCM. Therefore, targeting mitochondria for DCM will require better mechanistic characterization of morphological distortion and bioenergetic dysfunction. Antioxid. Redox Signal. 22, 1545Signal. 22, -1562

show abstract

Loss of Drp1 function alters OPA1 processing and changes mitochondrial membrane organization

Cited by 62 publications

References 46 publications

Perturbations in Mitochondrial Dynamics Induced by Human Mutant PINK1 Can Be Rescued by the Mitochondrial Division Inhibitor mdivi-1

Perturbations in Mitochondrial Dynamics Induced by Human Mutant PINK1 Can Be Rescued by the Mitochondrial Division Inhibitor mdivi-1

Higd-1a interacts with Opa1 and is required for the morphological and functional integrity of mitochondria

Mitochondrial Dynamics in Diabetic Cardiomyopathy

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