Mitochondrial dynamics in cell death and neurodegeneration

Cho, Dong‐Hyung; Nakamura, Tomohiro; Lipton, Stuart A.

doi:10.1007/s00018-010-0435-2

Cited by 265 publications

(208 citation statements)

References 162 publications

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“…Disruption of mitochondrial morphological dynamics sensitizes cells to apoptotic cell death (9,24,25), and recent studies have reported that disturbances within the balance of these two processes can implicate the outcome of cardiovascular disease and neurodegenerative disease (20). In this study, we show that ischemic challenge in myocytes promotes translocation of Drp1 to His-Pim-1 (wild-type, kinase dead) was expressed in Escherichia coli and affinitypurified for use in the kinase assay.…”

Section: Discussionmentioning

confidence: 77%

“…S1 D and E). Previous studies have shown that phosphorylation of Drp1-S637 reduces mitochondrial fragmentation, Drp1 accumulation at the mitochondria, and apoptotic cell death (19,20). Because we have established that Pim-1 kinase preserves mitochondrial integrity and function (15), we investigated whether Pim-1 expression could affect pDrp1-S637 levels.…”

Section: Drp1mentioning

confidence: 99%

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Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

Din

Mason

Völkers

et al. 2013

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

116

121

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Mitochondrial morphological dynamics affect the outcome of ischemic heart damage and pathogenesis. Recently, mitochondrial fission protein dynamin-related protein 1 (Drp1) has been identified as a mediator of mitochondrial morphological changes and cell death during cardiac ischemic injury. In this study, we report a unique relationship between Pim-1 activity and Drp1 regulation of mitochondrial morphology in cardiomyocytes challenged by ischemic stress. Transgenic hearts overexpressing cardiac Pim-1 display reduction of total Drp1 protein levels, increased phosphorylation of Drp1-S637 , and inhibition of Drp1 localization to the mitochondria. Consistent with these findings, adenoviral-induced Pim-1 neonatal rat cardiomyocytes (NRCMs) retain a reticular mitochondrial phenotype after simulated ischemia (sI) and decreased Drp1 mitochondrial sequestration. Interestingly, adenovirus Pimdominant negative NRCMs show increased expression of Bcl-2 homology 3 (BH3)-only protein p53 up-regulated modulator of apoptosis (PUMA), which has been previously shown to induce Drp1 accumulation at mitochondria and increase sensitivity to apoptotic stimuli. Overexpression of the p53 up-regulated modulator of apoptosis-dominant negative adenovirus attenuates localization of Drp1 to mitochondria in adenovirus Pim-dominant negative NRCMs promotes reticular mitochondrial morphology and inhibits cell death during sI. Therefore, Pim-1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology in response to sI.

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Section: Discussionmentioning

confidence: 77%

Section: Drp1mentioning

confidence: 99%

Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

Din

Mason

Völkers

et al. 2013

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

116

121

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“…Although cocaine-or alcohol-induced histone H3K4me3 changes were not directly predictive of gene expression at the individual gene promoter level, the observed histone H3K4me3 profiles still provide valuable insight into the addiction-induced alteration of histone structure. Mitochondrial inner membrane dysfunctions are known to play critical roles in neurodegenerative diseases such as Huntington disease, Alzheimer disease, and Parkinson disease (21). The main dysfunctions involved in the pathological processes are suppressed oxidative stress defense, altered membrane ion permeability, and, particularly, depleted ATP synthesis resulting from the inhibition of components of the oxidative phosphorylation pathway.…”

Section: Discussionmentioning

confidence: 99%

Substance-specific and shared transcription and epigenetic changes in the human hippocampus chronically exposed to cocaine and alcohol

Zhou

Yuan

Mash

et al. 2011

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

198

208

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The hippocampus is a key brain region involved in both short-and long-term memory processes and may play critical roles in drugassociated learning and addiction. Using whole genome sequencing of mRNA transcripts (RNA-Seq) and immunoprecipitation-enriched genomic DNA (ChIP-Seq) coupled with histone H3 lysine 4 trimethylation (H3K4me3), we found extensive hippocampal gene expression changes common to both cocaine-addicted and alcoholic individuals that may reflect neuronal adaptations common to both addictions. However, we also observed functional changes that were related only to long-term cocaine exposure, particularly the inhibition of mitochondrial inner membrane functions related to oxidative phosphorylation and energy metabolism, which has also been observed previously in neurodegenerative diseases. Cocaineand alcohol-related histone H3K4me3 changes highly overlapped, but greater effects were detected under cocaine exposure. There was no direct correlation, however, between either cocaine-or alcohol-related histone H3k4me3 and gene expression changes at an individual gene level, indicating that transcriptional regulation as well as drug-related gene expression changes are outcomes of a complex gene-regulatory process that includes multifaceted histone modifications.drug addiction | histone methylation K nowledge of the cellular and molecular adaptations underlying addiction to cocaine and alcohol has primarily been gained from animal models of acute and chronic drug exposure, from which specific molecular pathways to addiction have been identified (1, 2). Studies on human postmortem brain (3) have yielded data that are complementary and tend to validate animal models of exposure. Addiction-associated molecular alterations observed in animal and human studies are diverse. Clearly, cellular and molecular responses to addictive drugs depend on the type and timing of exposure, the timing of observations within the progression to addiction, and the brain regions and cells in which observations are made. Specific changes in signal transduction pathways, including in the transcription factor ΔFosB and the cAMP-response element binding protein (CREB), are likely to be more prominent in early stages of drug-induced neuroadaptation (4). Longstanding adaptations may be marked by changes in expression of genes involved in the regulation of cellular functions including ion transport, chromosome remodeling, stress and immune response, cell adhesion, cell cycle, apoptosis, protein and lipid metabolism, and mitochondrial functions (3). Later changes may be more closely relevant to addictive behaviors and long-lasting vulnerability to relapse.The hippocampus is also a brain region critically involved in addiction. Most studies have focused on the mesolimbic system, in which medium-sized spiny neurons in the dorsal striatum and nucleus accumbens mediate dopaminergic, glutamatergic, and GABAergic neurotransmission (5) and are key in drug-reward and drug-seeking behavior. However, hippocampal functions related to short-and long...

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“…Furthermore, the importance of mitochondrial dynamics has been documented in neuronal development (Li et al, 2004;Dickey and Strack, 2011;Chan, 2006;Ishihara et al, 2009) and survival Merrill et al, 2013;Dagda et al, 2008;Merrill et al, 2011;Cho et al, 2010;Nakamura et al, 2010). However, also there, the specific mechanisms often await elucidation.…”

Section: Introductionmentioning

confidence: 99%