Miro-1 Links Mitochondria and Microtubule Dynein Motors To Control Lymphocyte Migration and Polarity

Morlino, Giulia; Barreiro, Olga; Baixauli, Francesc; Robles‐Valero, Javier; González-Granado, José-María; Villa‐Bellosta, Ricardo; Cuenca, J.; Sánchez-Sorzano, Carlos Óscar; Veiga, Esteban; Martín-Cófreces, Noa B.; Sánchez-Madrid, Francisco

doi:10.1128/mcb.01177-13

Cited by 106 publications

(91 citation statements)

References 64 publications

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“…Although this process has been often considered ‘neuronal-specific'23, we now know that mitochondria travel along the microtubule network also in non-neuronal cells, supporting the motility of normal24, as well as transformed13 cell types in response to stress conditions of the microenvironment14.…”

Section: Discussionmentioning

confidence: 99%

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A neuronal network of mitochondrial dynamics regulates metastasis

et al. 2016

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The role of mitochondria in cancer is controversial. Using a genome-wide shRNA screen, we now show that tumours reprogram a network of mitochondrial dynamics operative in neurons, including syntaphilin (SNPH), kinesin KIF5B and GTPase Miro1/2 to localize mitochondria to the cortical cytoskeleton and power the membrane machinery of cell movements. When expressed in tumours, SNPH inhibits the speed and distance travelled by individual mitochondria, suppresses organelle dynamics, and blocks chemotaxis and metastasis, in vivo. Tumour progression in humans is associated with downregulation or loss of SNPH, which correlates with shortened patient survival, increased mitochondrial trafficking to the cortical cytoskeleton, greater membrane dynamics and heightened cell invasion. Therefore, a SNPH network regulates metastatic competence and may provide a therapeutic target in cancer.

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Section: Discussionmentioning

confidence: 99%

“…In addition, molecules known to regulate mitochondrial repositioning in neurons, including KIF5B30 and Miro1 (ref. 24) emerged here as novel modulators of organelle movements in the SNPH pathway in tumours. Conversely, another atypical mitochondrial GTPase, Miro2 (ref.…”

Section: Discussionmentioning

confidence: 99%

A neuronal network of mitochondrial dynamics regulates metastasis

et al. 2016

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“…, near the cytosolic membranes), without elevating overall cytosolic ATP levels (a costly process). Mitochondria have been shown to relocate at the edge of lamellipodia and are critical to provide energy for migration of cells (Morlino et al, 2014). Our studies reveal the presence of microenvironments where ATP/ADP accumulate in CD8 cells that are located in the proximity of mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Fine-Tuning of CD8 + T Cell Mitochondrial Metabolism by the Respiratory Chain Repressor MCJ Dictates Protection to Influenza Virus

et al. 2016

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SUMMARY Mitochondrial respiration is tightly regulated in CD8 T cells during the transition from naïve to effector and memory cells, but the mechanisms that control this process have not been defined. Here we show that MCJ/DnaJC15 acts as an endogenous break for mitochondrial respiration in CD8 T cells by interfering with the formation of electron transport chain (ETC) respiratory supercomplexes. Metabolic profiling reveals an enhanced mitochondrial metabolism in MCJ-deficient CD8 cells. Increased oxidative phosphorylation and subcellular ATP accumulation caused by the loss of MCJ selectively increase the secretion, but not the expression, of IFNγ. MCJ also serves to adapt effector CD8 T cell metabolism during the contraction phase. Consequently, memory CD8 cells lacking MCJ are superior in providing protection against influenza virus infection. Thus, MCJ offers a novel mechanism for fine-tuning mitochondrial metabolism in CD8 cells, as an alternative to modulating mitochondrial mass, which is an energetically expensive process. MCJ could be a new therapeutic target to enhance CD8 cell responses.

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“…Intracellular ATP concentration was measured as previously described [27]. Briefly, fresh H9C2 cells were homogenized with the lysis buffer.…”

Section: Methodsmentioning

confidence: 99%

Targeted deletion of PTEN in cardiomyocytes renders cardiac contractile dysfunction through interruption of Pink1–AMPK signaling and autophagy

Roe

Kandadi

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Phosphatase and tensin homolog deleted from chromosome 10 (PTEN) has been implicated in the maintenance of cardiac homeostasis although the underlying mechanism(s) remains elusive. We generated a murine model of cardiomyocyte-specific knockout of PTEN to evaluate cardiac geometry and contractile function, as well as the effect of metformin on PTEN deficiency-induced cardiac anomalies, if any. Cardiac histology, autophagy and related signaling molecules were evaluated. Cardiomyocyte-specific PTEN deletion elicited cardiac hypertrophy and contractile anomalies (echocardiographic and cardiomyocyte contractile dysfunction) associated with compromised intracellular Ca2+ handling. PTEN deletion-induced cardiac hypertrophy and contractile anomalies were associated with dampened phosphorylation of PTEN-inducible kinase 1 (Pink1) and AMPK. Interestingly, administration of AMPK activator metformin (200 mg/kg/d, in drinking H2O for 4 weeks) rescued against PTEN deletion-induced geometric and functional defects as well as interrupted autophagy and autophagic flux in the heart. Moreover, metformin administration partially although significantly attenuated PTEN deletion-induced accumulation of superoxide. RNA interference against Pink1 in H9C2 myoblasts overtly increased intracellular ATP levels and suppressed AMPK phosphorylation, confirming the role of AMPK as a downstream target for PTEN-Pink1. Further scrutiny revealed that activation of AMPK and autophagy using metformin and rapamycin, respectively, rescued against PTEN deletion-induced mechanical anomalies with little additive effect. These data demonstrated that cardiomyocyte-specific deletion of PTEN leads to the loss of Pink1-AMPK signaling, development of cardiac hypertrophy and contractile defect. Activation of AMPK rescued against PTEN deletion-induced cardiac anomalies associated with restoration of autophagy and autophagic flux.

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Miro-1 Links Mitochondria and Microtubule Dynein Motors To Control Lymphocyte Migration and Polarity

Cited by 106 publications

References 64 publications

A neuronal network of mitochondrial dynamics regulates metastasis

A neuronal network of mitochondrial dynamics regulates metastasis

Fine-Tuning of CD8 + T Cell Mitochondrial Metabolism by the Respiratory Chain Repressor MCJ Dictates Protection to Influenza Virus

Targeted deletion of PTEN in cardiomyocytes renders cardiac contractile dysfunction through interruption of Pink1–AMPK signaling and autophagy

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