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

Cui, Mei; Tang, X.; Christian, Whitney V.; Yoon, Yisang; Tieu, Kim

doi:10.1074/jbc.m109.066662

Cited by 178 publications

(163 citation statements)

References 52 publications

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“…From the previous study, we expected that the introduction of mdivi-1 could be used as a reliable tool to dissect the exact role of Drp1 throughout myogenic differentiation as it has already proven to be a selective, rapid, and reversible inhibitor of Drp1 with reduced indirect effects as opposed to genetically modified models using mutant, knockout cells, or RNAi techniques (34). Recently, mdivi-1 has emerged as a potential novel therapeutic compound for heart failure, cardiac ischemia-reperfusion injury, pulmonary hypertension, and Parkinson's disease (11,21,34,37,46). While it is too early to be conclusive, the results from our study provide an important insight into a potential adverse effect of mdivi-1 in myogenic differentiation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Drp1-dependent mitochondrial division impairs myogenic differentiation

Kim

Yoon

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Mitochondria are dynamic organelles forming a tubular network that is continuously fusing and dividing to control their morphology and functions. Recent literature has shed new light on a potential link between the dynamic behavior of mitochondria and muscle development. In this study, we investigate the role of mitochondrial fission factor dynamin-related protein 1 (Drp1) in myogenic differentiation. We found that differentiation of C2C12 myoblasts induced by serum starvation was accompanied by a gradual increase in Drp1 protein expression (to ∼350% up to 3 days) and a fast reduction of Drp1 phosphorylation at Ser-637 (to ∼30%) resulting in translocation of Drp1 protein from the cytosol to mitochondria. During differentiation, treatment of myoblasts with mitochondrial division inhibitor ( mdivi-1), a specific inhibitor of Drp1 GTPase activity, caused extensive formation of elongated mitochondria, which coincided with increased apoptosis evidenced by both enhanced caspase-3 activity and increased number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells. Furthermore, the mdivi-1-treated myotubes ( day 3 in differentiation media) showed a reduction in mitochondrial DNA content, mitochondrial mass, and membrane potential in a dose-dependent manner indicating defects in mitochondrial biogenesis during myogenic differentiation. Most interestingly, mdivi-1 treatment significantly suppressed myotube formation in both C2C12 cells and primary myoblasts. Likewise, stable overexpression of a dominant negative mutant Drp1 (K38A) dramatically reduced myogenic differentiation. These data suggest that Drp-1-dependent mitochondrial division is a necessary step for successful myogenic differentiation, and perturbation of mitochondrial dynamics hinders normal mitochondrial adaptations during muscle development. Therefore, in the present study, we report a novel physiological role of mitochondrial dynamics in myogenic differentiation.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Drp1-dependent mitochondrial division impairs myogenic differentiation

Kim

Yoon

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…We did not observe any significant increases in Light Chain 3B (LC3B) staining in permeabilized OT-I T cells, suggesting that autophagic processes are likely not overtly deregulated in these cells ( Figure 3D). We also treated tumor-bearing mice 24 hr after transfer with the mitophagy and mitochondrial fission inhibitor m-divi-1 (Cui et al, 2010); this also failed to improve mitochondrial staining in tumor infiltrating T cells ( Figure 3E). We also asked whether loss of mitochondrial function could occur in vitro in response to co-culture with tumor cells, and found that response of naive or previously activated OT-I T cells to B16 OVA tumor cells in vitro did not result in mitochondrial loss (Figures S3A and S3B).…”

Section: Mitochondria Become Dysfunctional As T Cells Are Activated Imentioning

confidence: 99%

The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction

Scharping¹,

Menk²,

Moreci³

et al. 2016

Immunity

397

171

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SUMMARYAlthough tumor-specific T cells recognize cancer cells, they are often rendered dysfunctional due to an immunosuppressive microenvironment. Here we showed that T cells demonstrated persistent loss of mitochondrial function and mass when infiltrating murine and human tumors, an effect specific to the tumor microenvironment and not merely caused by activation. Tumor-infiltrating T cells showed a progressive loss of PPAR-gamma coactivator 1α (PGC1α), which programs mitochondrial biogenesis, induced by chronic Akt signaling in tumor-specific T cells. Reprogramming tumor-specific T cells through enforced expression of PGC1α resulted in superior intratumoral metabolic and effector function. Our data support a model in which signals in the tumor microenvironment repress T cell oxidative metabolism, resulting in effector cells with metabolic needs that cannot be met. Our studies also suggest that modulation or reprogramming of the altered metabolism of tumor-infiltrating T cells might represent a potential strategy to reinvigorate dysfunctional T cells for cancer treatment. Abstract * Correspondence: gdelgoffe@pitt.edu.

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“…Knockdown of Parkin results in mitochondrial elongation in flies (40). However, studies in mammalian cells suggest that loss of Parkin/PINK1 function may lead to excess mitochondria fragmentation or enhanced mitochondrial biogenesis (45)(46)(47)(48). We thus sought to address the molecular details on how Parkin regulates mitochondrial fission and fusion in mammalian systems.…”

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confidence: 99%

Parkin Ubiquitinates Drp1 for Proteasome-dependent Degradation

Wang

Song

et al. 2011

Journal of Biological Chemistry

321

172

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Mutations in Parkin, an E3 ubiquitin ligase that regulates protein turnover, represent one of the major causes of familial Parkinson disease, a neurodegenerative disorder characterized by the loss of dopaminergic neurons and impaired mitochondrial functions. The underlying mechanism by which pathogenic Parkin mutations induce mitochondrial abnormality is not fully understood. Here, we demonstrate that Parkin interacts with and subsequently ubiquitinates dynamin-related protein 1 (Drp1), for promoting its proteasome-dependent degradation. Pathogenic mutation or knockdown of Parkin inhibits the ubiquitination and degradation of Drp1, leading to an increased level of Drp1 for mitochondrial fragmentation. These results identify Drp1 as a novel substrate of Parkin and suggest a potential mechanism linking abnormal Parkin expression to mitochondrial dysfunction in the pathogenesis of Parkinson disease. Parkinson disease (PD)4 is one of the most common neurodegenerative diseases affecting over 2% populations over 65 years of age. It is classically characterized by the loss of dopaminergic neurons that project from the midbrain substantia nigra to the striatum (1, 2). Although the loss of dopaminergic neurons is responsible for the symptom of movement disorder in PD, it is now clear that other types of neurons throughout the brain are also affected in the disease (3, 4). The identification of genes linking to PD has greatly advanced our understanding of the molecular pathogenesis of the disease (5-8). Mutations in Parkin represent one of major causes for early onset of familial PD (9 -11). Parkin is an E3 ubiquitin ligase that contains two ring finger domains (12-15). A handful of substrates have been identified, including Parkin itself and CDCrel-1, synphilin-1, Pael-R, glycosylated ␣-synuclein, FBP1 (far upstream elementbinding protein 1), and the RNA-processing protein subunit p38/AIMP2 (16 -19). A putative mechanism by which mutations of Parkin cause PD would be abnormal accumulation and aggregation of the above substrates due to insufficient E3 ligase activity for ubiquitin-proteasome-dependent protein turnover (18,20,21). Surprisingly, only p38/AIMP2 and FBP1 were found to be accumulated in the brain samples of PD patients or in Parkin knock-out mice (16,17,19). Even though a number of the putative substrates have been identified, the causative link between these substrates and the PD pathogenesis remains not fully understood.Over the past few decades, accumulating evidence has suggested that mitochondrial dysfunction and the resulting oxidative damage are associated with PD. This is supported by a large number of reports demonstrating impaired mitochondrial functions in PD patients (22)(23)(24)(25)(26). Mitochondria undergo frequent fission, fusion, and redistribution throughout the cytoplasm in response to the energy needs (27,28). Either disruption of the fusion process or enhancement of the fission process renders the normal, tubular network of mitochondria to fragment into short rods or spheres (29). Abnormal...

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

Cited by 178 publications

References 52 publications

Inhibition of Drp1-dependent mitochondrial division impairs myogenic differentiation

Inhibition of Drp1-dependent mitochondrial division impairs myogenic differentiation

The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction

Parkin Ubiquitinates Drp1 for Proteasome-dependent Degradation

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