Search

Inherited optic neuropathies are the most common mitochondrial diseases, leading to neurodegeneration involving the irreversible loss of retinal ganglion cells, optic nerve degeneration and central visual loss. Importantly, properly regulated mitochondrial dynamics are critical for maintaining cellular homeostasis, and are further regulated by MIEF1 (mitochondrial elongation factor 1) which encodes for MID51 (mitochondrial dynamics protein 51), an outer mitochondrial membrane protein that acts as an adaptor protein to regulate mitochondrial fission. However, dominant mutations in MIEF1 have not been previously linked to any human disease. Using targeted sequencing of genes involved in mitochondrial dynamics, we report the first heterozygous variants in MIEF1 linked to disease, which cause an unusual form of late-onset progressive optic neuropathy characterized by the initial loss of peripheral visual fields. Pathogenic MIEF1 variants linked to optic neuropathy do not disrupt MID51’s localization to the outer mitochondrial membrane or its oligomerization, but rather, significantly disrupt mitochondrial network dynamics compared to wild-type MID51 in high spatial and temporal resolution confocal microscopy live imaging studies. Together, our study identifies dominant MIEF1 mutations as a cause for optic neuropathy and further highlights the important role of properly regulated mitochondrial dynamics in neurodegeneration.

The role of miRNAs in determining human neural stem cell (NSC) fate remains elusive despite their high expression in the developing nervous system. In this study, we investigate the role of miR‐137, a brain‐enriched miRNA, in determining the fate of human induced pluripotent stem cells‐derived NSCs (hiNSCs). We show that ectopic expression of miR‐137 in hiNSCs reduces proliferation and accelerates neuronal differentiation and migration. TargetScan and MicroT‐CDS predict myocyte enhancer factor‐2A (MEF2A), a transcription factor that regulates peroxisome proliferator‐activated receptor‐gamma coactivator (PGC1α) transcription, as a target of miR‐137. Using a reporter assay, we validate MEF2A as a downstream target of miR‐137. Our results indicate that reduced levels of MEF2A reduce the transcription of PGC1α, which in turn impacts mitochondrial dynamics. Notably, miR‐137 accelerates mitochondrial biogenesis in a PGC1α independent manner by upregulating nuclear factor erythroid 2 (NFE2)‐related factor 2 (NRF2) and transcription factor A of mitochondria (TFAM). In addition, miR‐137 modulates mitochondrial dynamics by inducing mitochondrial fusion and fission events, resulting in increased mitochondrial content and activation of oxidative phosphorylation (OXPHOS) and oxygen consumption rate. Pluripotency transcription factors OCT4 and SOX2 are known to have binding sites in the promoter region of miR‐137 gene. Ectopic expression of miR‐137 elevates the expression levels of OCT4 and SOX2 in hiNSCs which establishes a feed‐forward self‐regulatory loop between miR‐137 and OCT4/SOX2. Our study provides novel molecular insights into NSC fate determination by miR‐137., miR‐137 facilitates neuronal differentiation of neural stem cells by enhancing mitochondrial biogenesis, fusion, fission, and OXPHOS. miR‐137 downregulates MEF2A, which may reduce the transcription of PGC1α. Increased expression of nuclear factor erythroid 2 (NFE2)‐related factor 2 (NRF2) and transcription factor A of mitochondria (TFAM) by miR‐137 elevates mitochondrial biogenesis to match the need of newly generated neurons.

Current cancer therapies are successfully increasing the lifespan of cancer patients. Nevertheless, cardiotoxicity is a serious chemotherapy-induced adverse side effect. Doxorubicin (DOX) and mitoxantrone (MTX) are cardiotoxic anticancer agents, whose toxicological mechanisms are still to be identified. This study focused on DOX and MTX’s cardiac mitochondrial damage and their molecular mechanisms. As a hypothesis, we also sought to compare the cardiac modulation caused by 9 mg/kg of DOX or 6 mg/kg of MTX in young adult mice (3 months old) with old control mice (aged control, 18–20 months old) to determine if DOX- and MTX-induced damage had common links with the aging process. Cardiac homogenates and enriched mitochondrial fractions were prepared from treated and control animals and analyzed by immunoblotting and enzymatic assays. Enriched mitochondrial fractions were also characterized by mass spectrometry-based proteomics. Data obtained showed a decrease in mitochondrial density in young adults treated with DOX or MTX and aged control, as assessed by citrate synthase (CS) activity. Furthermore, aged control had increased expression of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α) and manganese superoxide dismutase (MnSOD). Regarding the enriched mitochondrial fractions, DOX and MTX led to downregulation of proteins related to oxidative phosphorylation, fatty acid oxidation, amino acid metabolic process, and tricarboxylic acid cycle. MTX had a greater impact on malate dehydrogenase (MDH2) and pyruvate dehydrogenase E1 component subunit α (PDHA1). No significant proteomic changes were observed in the enriched mitochondrial fractions of aged control when compared to young control. To conclude, DOX and MTX promoted changes in several mitochondrial-related proteins in young adult mice, but none resembling the aged phenotype.

D620N mutation in the vacuolar protein sorting 35 ortholog (VPS35) gene causes late‐onset, autosomal dominant familial Parkinson's disease (PD) and contributes to idiopathic PD. However, how D620N mutation leads to PD‐related deficits in vivo remains unclear. In the present study, we thoroughly characterized the biochemical, pathological, and behavioral changes of a VPS35 D620N knockin (KI) mouse model with chronic aging. We reported that this VPS35 D620N KI model recapitulated a spectrum of cardinal features of PD at 14 months of age which included age‐dependent progressive motor deficits, significant changes in the levels of dopamine (DA) and DA metabolites in the striatum, and robust neurodegeneration of the DA neurons in the SNpc and DA terminals in the striatum, accompanied by increased neuroinflammation, and accumulation and aggregation of α‐synuclein in DA neurons. Mechanistically, D620N mutation induced mitochondrial fragmentation and dysfunction in aged mice likely through enhanced VPS35‐DLP1 interaction and increased turnover of mitochondrial DLP1 complexes in vivo. Finally, the VPS35 D620N KI mice displayed greater susceptibility to MPTP‐mediated degeneration of nigrostriatal pathway, indicating that VPS35 D620N mutation increased vulnerability of DA neurons to environmental toxins. Overall, this VPS35 D620N KI mouse model provides a powerful tool for future disease modeling and pharmacological studies of PD. Our data support the involvement of VPS35 in the development of α‐synuclein pathology in vivo and revealed the important role of mitochondrial fragmentation/dysfunction in the pathogenesis of VPS35 D620N mutation‐associated PD in vivo., Homozygous VPS35 D620N KI mice recapitulate cardinal features of PD including motor deficits, dopaminergic neuronal loss, and reduced dopamine along with accumulation and aggregation of α‐synuclein in an age‐dependent manner. VPS35 D620N mutation induced mitochondrial fragmentation and dysfunction through enhanced VPS35‐DLP1 interaction and increased turnover of mitochondrial DLP1 complexes in vivo. VPS35 D620N KI mice displayed greater susceptibility to PD‐related neurotoxin of MPTP.

GPRASP (GPCR-associated sorting protein)/ARMCX (ARMadillo repeat-Containing proteins on the X chromosome) family is composed of 10 proteins, whose genes are located on a small locus of the X chromosome except one. They possess at least two armadillo-like repeats on their carboxylterminal homologous sequence, but they can be subdivided on specific sequence features. Subfamily 1 (GPRASP1, GPRASP2, GPRASP3, ARMCX4 and ARMCX5) displays additional repeated motifs while a mitochondrial targeting transmembrane domain is present in subfamily 2 (ARMC10, ARMCX1, ARMCX2, ARMCX3 and ARMCX6). Although their roles are not yet fully understood, the recent identification of several interacting partners has shed new light on the processes in which GPRASP/ARMCX proteins are implicated. Among the interacting partners of proteins from subfamily 1, many are GPCRs. GPRASP1 binds trafficking proteins, such as Beclin2 and the Dysbindin-HRS-Gαs complex, to participate in GPCR post-endocytic sorting. Moreover, in vitro as well as in vivo experiments indicate that GPRASP1 is a critical player in the adaptive responses related to chronic treatments with GPCR agonists. GPRASP2 seems to play a key role in the signaling of the hedgehog pathway in the primary cilium through a Smoothened-GPRASP2-Pifo complex. Identified small compound inhibitors of this complex could treat drug-resistant smoothened derived cancer forms. Deletion of GPRASP2 in mice causes neurodevelopmental alteration and affects mGluR5 regulation, reflected by autism-like behavior. Several members of subfamily 2, in complex with TRAK2 and MIRO, are involved in the trafficking of mitochondria in axons and in the regulation of their size and division, influencing the cell cycle. The essential role of GPRASP/ARMCX proteins in cellular physiology is supported by human cases of deletions, causing male neonatal lethality by pulmonary delayed development, dysmorphic face, and psychiatric and intellectual impacts in females.

International audience; OPA1 is a GTPase that controls several functions, such as mitochondrial dynamics and energetics, mtDNA maintenance and cristae integrity. In the last years, there have been described other cellular pathways and mechanisms involving OPA1 directly or through its interaction. All this new information, by implementing our knowledge on OPA1 is instrumental to elucidating the pathogenic mechanisms of OPA1 mutations. Indeed, these are associated with dominant optic atrophy (DOA), one of the most common inherited optic neuropathies, and with an increasing number of heterogeneous neurodegenerative disorders. In this review, we overview all recent findings on OPA1 protein functions, on its dysfunction and related clinical phenotypes, focusing on the current therapeutic options and future perspectives to treat DOA and the other associated neurological disorders due to OPA1 mutations.

Simple Summary Mitochondria are well known for being the powerhouses of the cell—whether the cell is normal or cancerous. Moreover, they can move, split, fuse themselves, or be eliminated via mitophagy with the help of the interplay between motor proteins and the cell scaffold—especially microtubules. The relationship between mitochondria, microtubules, and motor proteins is altered in cancer, and targeting this molecular machinery can offer a novel weapon in its treatment. In this paper, we review and summarize the state of the art of this approach. Abstract Mitochondria constitute an ever-reorganizing dynamic network that plays a key role in several fundamental cellular functions, including the regulation of metabolism, energy production, calcium homeostasis, production of reactive oxygen species, and programmed cell death. Each of these activities can be found to be impaired in cancer cells. It has been reported that mitochondrial dynamics are actively involved in both tumorigenesis and metabolic plasticity, allowing cancer cells to adapt to unfavorable environmental conditions and, thus, contributing to tumor progression. The mitochondrial dynamics include fusion, fragmentation, intracellular trafficking responsible for redistributing the organelle within the cell, biogenesis, and mitophagy. Although the mitochondrial dynamics are driven by the cytoskeleton—particularly by the microtubules and the microtubule-associated motor proteins dynein and kinesin—the molecular mechanisms regulating these complex processes are not yet fully understood. More recently, an exchange of mitochondria between stromal and cancer cells has also been described. The advantage of mitochondrial transfer in tumor cells results in benefits to cell survival, proliferation, and spreading. Therefore, understanding the molecular mechanisms that regulate mitochondrial trafficking can potentially be important for identifying new molecular targets in cancer therapy to interfere specifically with tumor dissemination processes.

Mitochondria play pivotal roles in the ATP production, apoptosis and generation of reactive oxygen species. Although dynamic regulation of mitochondria morphology is a critical step to maintain cellular homeostasis, the regulatory mechanisms are not yet fully elucidated. In this study, we identified miR-200a-3p as a novel regulator of mitochondrial dynamics by targeting mitochondrial fission factor (MFF). We demonstrated that the ectopic expression of miR-200a-3p enhanced mitochondrial elongation, mitochondrial ATP synthesis, mitochondrial membrane potential and oxygen consumption rate. These results indicate that miR-200a-3p positively regulates mitochondrial elongation by downregulating MFF expression. [BMB Reports 2017; 50(4): 214-219].

Orderly mitochondrial life cycle, plays a key role in the pathology of neurodegenerative diseases. Mitochondria are ubiquitous in neurons as they respond to an ever-changing demand for energy supply. Mitochondria constantly change in shape and location, feature of their dynamic nature, which facilitates a quality control mechanism. Biological studies in mitochondria dynamics are unveiling the mechanisms of fission and fusion, which essentially arrange morphology and motility of these organelles. Control of mitochondrial network homeostasis is a critical factor for the proper function of neurons. Disease-related genes have been reported to be implicated in mitochondrial dysfunction. Increasing evidence implicate mitochondrial perturbation in neuronal diseases, such as AD, PD, HD, and ALS. The intricacy involved in neurodegenerative diseases and the dynamic nature of mitochondria point to the idea that, despite progress toward detecting the biology underlying mitochondrial disorders, its link to these diseases is difficult to be identified in the laboratory. Considering the need to model signaling pathways, both in spatial and temporal level, there is a challenge to use a multiscale modeling framework, which is essential for understanding the dynamics of a complex biological system. The use of computational models in order to represent both a qualitative and a quantitative structure of mitochondrial homeostasis, allows to perform simulation experiments so as to monitor the conformational changes, as well as the intersection of form and function.

// Xingchun Gao 1, 2, * , Yajing Mi 1, * , Na Guo 1, * , Zhifang Hu 1 , Fengrui Hu 1 , Dou liu 1 , Lei Gao 1 , Xingchun Gou 1 , Weilin Jin 1, 2, 3 1 Institute of Basic Medical Sciences and Shaanxi key Laboratory of ischemic Cardiovascular Disease, Xi’an Medical University, Xi’an 710021, P. R. China 2 Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Lab. for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China 3 National Centers for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China * These authors contributed equally to this work Correspondence to: Xingchun Gou, email: gouxingchun@189.cn Weilin Jin, email: weilinjin@yahoo.com , weilinjin@sjtu.edu.cn Keywords: glioblastoma, DISC1, mitochondria dynamics, self-renewal, Drp1 Received: August 15, 2016 Accepted: November 07, 2016 Published: November 11, 2016 ABSTRACT Glioblastoma(GBM) is one of the most common and aggressive malignant primary tumors of the central nervous system and mitochondria have been proposed to participate in GBM tumorigenesis. Previous studies have identified a potential role of Disrupted in Schizophrenia 1 (DISC1), a multi-compartmentalized protein, in mitochondria. But whether DISC1 could regulate GBM tumorigenesis via mitochondria is still unknown. We determined the expression level of DISC1 by both bioinformatics analysis and tissue analysis, and found that DISC1 was highly expressed in GBM. Knocking down of DISC1 by shRNA in GBM cells significantly inhibited cell proliferation both in vitro and in vivo . In addition, down-regulation of DISC1 decreased cell migration and invasion of GBM and self renewal capacity of glioblastoma stem-like cells. Furthermore, multiple independent rings or spheres could be observed in mitochondria in GBM depleted of DISC1, while normal filamentous morphology was observed in control cells, demonstrating that DISC1 affected the mitochondrial dynamic. Dynamin-related protein 1 (Drp1) was reported to contribute to mitochondrial dynamic regulation and influence glioma cells proliferation and invasion by RHOA/ ROCK1 pathway. Our data showed a significant decrease of Drp1 both in mRNA and protein level in GBM lack of DISC1, indicating that DISC1 maybe affect the mitochondrial dynamic by regulating Drp1. Taken together, our findings reveal that DISC1 affects glioblastoma cell development via mitochondria dynamics partly by down regulation of Drp1.

Circadian rhythms provide a selective advantage by anticipating organismal nutrient needs and guaranteeing optimal metabolic capacity during active hours. Impairment of circadian rhythms is associated with increased risk of type 2 diabetes and emerging evidence suggests that metabolic diseases are linked to perturbed clock machinery. The circadian clock regulates many transcriptional–translational processes influencing whole cell metabolism and particularly mitochondrial activity. In this review, we survey the current literature related to cross-talks between mitochondria and the circadian clock and unravel putative molecular links. Understanding the mechanisms that link metabolism and circadian responses to transcriptional modifications will provide valuable insights toward innovative therapeutic strategies to combat the development of metabolic disease.

Vascular progenitor cells (VPCs) present in the adventitia of the vessel wall play a critical role in the regulation of vascular repair following injury. This study aimed to assess the function of VPCs isolated from patients with Marfan syndrome (MFS). VPCs were isolated from control and MFS donors and characterized. Compared with control‐VPCs, MFS‐VPCs exhibited cellular senescence as demonstrated by increased cell size, higher SA‐β‐gal activity and elevated levels of p53 and p21. RNA sequencing showed that several cellular process‐related pathways including cell cycle and cellular senescence were significantly enriched in MFP‐VPCs. Notably, the expression level of TGF‐β1 was much higher in MFS‐VPCs than control‐VPCs. Treatment of control‐VPCs with TGF‐β1 significantly enhanced mitochondrial reactive oxidative species (ROS) and induced cellular senescence whereas inhibition of ROS reversed these effects. MFS‐VPCs displayed increased mitochondrial fusion and decreased mitochondrial fission. Treatment of control‐VPCs with TGF‐β1 increased mitochondrial fusion and reduced mitochondrial fission. Nonetheless, treatment of mitofusin2 (Mfn2)‐siRNA inhibited TGF‐β1‐induced mitochondrial fusion and cellular senescence. Furthermore, TGF‐β1‐induced mitochondrial fusion was mediated by the AMPK signalling pathway. Our study shows that TGF‐β1 induces VPC senescence in patients with MFS by mediating mitochondrial dynamics via the AMPK signalling pathway.

Background Maternal overnutrition including pre-pregnancy, pregnancy and lactation promotes a lipotoxic insult leading to metabolic dysfunction in offspring. Diet-induced obesity models (DIO) show that changes in hypothalamic mitochondria fusion and fission dynamics modulate metabolic dysfunction. Using three selective diet formula including a High fat diet (HFD), Cafeteria (CAF) and High Sugar Diet (HSD), we hypothesized that maternal diets exposure program leads to selective changes in hypothalamic mitochondria fusion and fission dynamics in male offspring leading to metabolic dysfunction which is exacerbated by a second exposure after weaning. Methods We exposed female Wistar rats to nutritional programming including Chow, HFD, CAF, or HSD for 9 weeks (pre-mating, mating, pregnancy and lactation) or to the same diets to offspring after weaning. We determined body weight, food intake and metabolic parameters in the offspring from 21 to 60 days old. Hypothalamus was dissected at 60 days old to determine mitochondria-ER interaction markers by mRNA expression and western blot and morphology by transmission electron microscopy (TEM). Mitochondrial-ER function was analyzed by confocal microscopy using hypothalamic cell line mHypoA-CLU192. Results Maternal programming by HFD and CAF leads to failure in glucose, leptin and insulin sensitivity and fat accumulation. Additionally, HFD and CAF programming promote mitochondrial fusion by increasing the expression of MFN2 and decreasing DRP1, respectively. Further, TEM analysis confirms that CAF exposure after programing leads to an increase in mitochondria fusion and enhanced mitochondrial-ER interaction, which partially correlates with metabolic dysfunction and fat accumulation in the HFD and CAF groups. Finally, we identified that lipotoxic palmitic acid stimulus in hypothalamic cells increases Ca2+ overload into mitochondria matrix leading to mitochondrial dysfunction. Conclusions We concluded that maternal programming by HFD induces hypothalamic mitochondria fusion, metabolic dysfunction and fat accumulation in male offspring, which is exacerbated by HFD or CAF exposure after weaning, potentially due to mitochondria calcium overflux.

Spinocerebellar ataxia type 3 (SCA3), known as Machado-Joseph disease, is an autosomal dominant disease caused by an abnormal expansion of polyglutamine in ATXN3 gene, leading to neurodegeneration in SCA3 patients. Similar to other neurodegenerative diseases, the dysfunction of mitochondria is observed to cause neuronal death in SCA3 patients. Based on previous studies, proteolytic cleavage of mutant ATXN3 is found to produce truncated C-terminal fragments in SCA3 models. However, whether these truncated mutant fragments disturb mitochondrial functions and result in pathological death is still unclear. Here, we used neuroblastoma cell and transgenic mouse models to examine the effects of truncated mutant ATXN3 on mitochondria functions. In different models, we observed truncated mutant ATXN3 accelerated the formation of aggregates, which translocated into the nucleus to form intranuclear aggregates. In addition, truncated mutant ATXN3 caused more mitochondrial fission, and decreased the expression of mitochondrial fusion markers, including Mfn-1 and Mfn-2. Furthermore, truncated mutant ATXN3 decreased the mitochondrial membrane potential, increased reactive oxygen species and finally increased cell death rate. In transgenic mouse models, truncated mutant ATXN3 also led to more mitochondrial dysfunction, neurodegeneration and cell death in the cerebellums. This study supports the toxic fragment hypothesis in SCA3, and also provides evidence that truncated mutant ATXN3 is severer than full-length mutant one in vitro and in vivo.

Fullerene (C60) derivatives, a unique class of compounds with potent antioxidant properties, have been reported to exert a wide variety of biological activities including neuroprotective properties. Mitochondrial dynamics are an important constituent of cellular quality control and function, and an imbalance of the dynamics eventually leads to mitochondria disruption and cell dysfunctions. This study aimed to assess the effects of carboxylic acid C60 derivatives (C60–COOH) on mitochondrial dynamics and elucidate its associated mechanisms in lipopolysaccharide (LPS)-stimulated BV-2 microglial cell model. Using a cell-based functional screening system labeled with DsRed2-mito in BV-2 cells, we showed that LPS stimulation led to excessive mitochondrial fission, increased mitochondrial localization of dynamin-related protein 1 (Drp1), both of which were markedly suppressed by C60–COOH pretreatment. LPS-induced mitochondria reactive oxygen species (ROS) generation and collapse of mitochondrial membrane potential (ΔΨm) were also significantly inhibited by C60–COOH. Moreover, we also found that C60–COOH pretreatment resulted in the attenuation of LPS-mediated activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling, as well as the production of pro-inflammatory mediators. Taken together, these findings demonstrated that carboxylic acid C60 derivatives may exert neuroprotective effects through regulating mitochondrial dynamics and functions in microglial cells, thus providing novel insights into the mechanisms of the neuroprotective properties of carboxylic acid C60 derivatives.

// Ting-Fang Che 1 , Ching-Wen Lin 2 , Yi-Ying Wu 5 , Yu-Ju Chen 6 , Chia-Li Han 7 , Yih-leong Chang 8 , Chen-Tu Wu 8 , Tzu-Hung Hsiao 9 , Tse-Ming Hong 5, * , Pan-Chyr Yang 1, 2, 3, 4, * 1 Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan 2 Institute of Biomedical Science, Academia Sinica, Taipei 115, Taiwan 3 NTU Center for Genomic Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan 4 Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan 5 Institute of Clinical Medicine, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan 6 Institute of Chemistry, Academia Sinica 115, Taipei, Taiwan 7 Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University 110, Taipei, Taiwan 8 Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 100, Taiwan 9 Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan * These authors have contributed equally to this work Correspondence to: Pan-Chyr Yang, e-mail: pcyang@ntu.edu.tw Tse-Ming Hong, e-mail: tmhong@mail.ncku.edu.tw Keywords: cancer metastasis, EGFR, mitochondria dynamics Received: May 19, 2015 Accepted: October 06, 2015 Published: October 19, 2015 ABSTRACT Dysfunction of the mitochondria is well-known for being associated with cancer progression. In the present study, we analyzed the mitochondria proteomics of lung cancer cell lines with different invasion abilities and found that EGFR is highly expressed in the mitochondria of highly invasive non-small-cell lung cancer (NSCLC) cells. EGF induces the mitochondrial translocation of EGFR; further, it leads to mitochondrial fission and redistribution in the lamellipodia, upregulates cellular ATP production, and enhances motility in vitro and in vivo . Moreover, EGFR can regulate mitochondrial dynamics by interacting with Mfn1 and disturbing Mfn1 polymerization. Overexpression of Mfn1 reverses the phenotypes resulting from EGFR mitochondrial translocation. We show that the mitochondrial EGFR expressions are higher in paired samples of the metastatic lymph node as compared with primary lung tumor and are inversely correlated with the overall survival in NSCLC patients. Therefore, our results demonstrate that besides the canonical role of EGFR as a receptor tyrosine, the mitochondrial translocation of EGFR may enhance cancer invasion and metastasis through regulating mitochondria dynamics.

Differentiation and dedifferentiation of vascular smooth muscle cells (VSMCs) are essential processes of vascular development. VSMC have biosynthetic, proliferative, and contractile roles in the vessel wall. Alterations in the differentiated state of the VSMC play a critical role in the pathogenesis of a variety of cardiovascular diseases, including atherosclerosis, hypertension, and vascular stenosis. This review provides an overview of the current state of knowledge of molecular mechanisms involved in the control of VSMC proliferation, with particular focus on mitochondrial metabolism. Mitochondrial activity can be controlled by regulating mitochondrial dynamics, i.e., mitochondrial fusion and fission, and by regulating mitochondrial calcium handling through the interaction with the endoplasmic reticulum (ER). Alterations in both VSMC proliferation and mitochondrial function can be triggered by dysregulation of mitofusin-2, a small GTPase associated with mitochondrial fusion and mitochondrial–ER interaction. Several lines of evidence highlight the relevance of mitochondrial metabolism in the control of VSMC proliferation, indicating a new area to be explored in the treatment of vascular diseases.

Evidence suggests a striking causal relationship between changes in quality control of neuronal mitochondria and numerous devastating human neurodegenerative diseases, including Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Hungtington’ Disease (HD) and amyotrophic lateral sclerosis (ALS). Contrary to replicating mammalian cells with a metabolism essentially glycolitic, post-mitotic neurons are distinctive owing to (i) their exclusive energetic dependence from mitochondrial metabolism and (ii) their polarized shape, which entails compartmentalized and distinct energetic needs. Here, we review the recent findings on mitochondrial dynamics and mitophagy in differentiated neurons focusing on how the exceptional characteristics of neuronal populations in their morphology and bioenergetics needs make them quite different to other cells in controlling the intracellular turnover of these organelles.

Excessive mitochondrial fission is associated with the pathogenesis of neurodegenerative diseases. Dynamin-related protein 1 (Drp1) possesses specific fission activity in the mitochondria and peroxisomes. Various post-translational modifications of Drp1 are known to modulate complex mitochondrial dynamics. However, the post-transcriptional regulation of Drp1 remains poorly understood. Here, we show that the heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) regulates Drp1 expression at the post-transcriptional level. hnRNP A1 directly interacts with Drp1 mRNA at its 3′UTR region, and enhances translation potential without affecting mRNA stability. Down-regulation of hnRNP A1 induces mitochondrial elongation by reducing Drp1 expression. Moreover, depletion of hnRNP A1 suppresses 3-NP-mediated mitochondrial fission and dysfunction. In contrast, over-expression of hnRNP A1 promotes mitochondrial fragmentation by increasing Drp1 expression. Additionally, hnRNP A1 significantly exacerbates 3-NP-induced mitochondrial dysfunction and cell death in neuroblastoma cells. Interestingly, treatment with 3-NP induces subcellular translocation of hnRNP A1 from the nucleus to the cytoplasm, which accelerates the increase in Drp1 expression in hnRNP A1 over-expressing cells. Collectively, our findings suggest that hnRNP A1 controls mitochondrial dynamics by post-transcriptional regulation of Drp1., Highlights • hnRNP A1 increases Drp1 expression through the interaction with 3′UTR of Drp1 mRNA. • Down-regulation of hnRNP A1 increases mitochondrial elongation by reducing drp1 expression. • Down-regulation of hnRNPA1 inhibits 3-NP-mediated mitochondrial dysfunction. • Over-expression of hnRNP A1 potentiates 3-NP-mediated mitochondrial dysfunction and cell death. • Treatment of 3-NP promotes translocation of hnRNP A1 to the cytoplasm and enhances Drp1 expression.

In Parkinson's disease mitochondrial dysfunction can lead to a deficient ATP supply to microtubule protein motors leading to mitochondrial axonal transport disruption. Compromised axonal transport will then lead to a disorganized distribution of mitochondria and other organelles in the cell, as well as, the accumulation of aggregated proteins like alpha-synuclein. Moreover, axonal transport disruption can trigger synaptic accumulation of autophagosomes packed with damaged mitochondria and protein aggregates promoting synaptic failure.We previously observed that neuronal-like cells with an inherent mitochondrial impairment derived from PD patients contain a disorganized microtubule network, as well as, alpha-synuclein oligomer accumulation. In this work we provide new evidence that an agent that promotes microtubule network assembly, NAP (davunetide), improves microtubule-dependent traffic, restores the autophagic flux and potentiates autophagosome–lysosome fusion leading to autophagic vacuole clearance in Parkinson's disease cells. Moreover, NAP is capable of efficiently reducing alpha-synuclein oligomer content and its sequestration by the mitochondria. Most interestingly, NAP decreases mitochondrial ubiquitination levels, as well as, increases mitochondrial membrane potential indicating a rescue in mitochondrial function.Overall, we demonstrate that by improving microtubule-mediated traffic, we can avoid mitochondrial-induced damage and thus recover cell homeostasis. These results prove that NAP may be a promising therapeutic lead candidate for neurodegenerative diseases that involve axonal transport failure and mitochondrial impairment as hallmarks, like Parkinson's disease and related disorders.