AMP-activated protein kinase mediates mitochondrial fission in response to energy stress

Toyama, Erin Quan; Herzig, Sébastien; Courchet, Julien; Lewis, Tommy L.; Losón, Oliver C.; Hellberg, Kristina; Young, Nathan P.; Chen, Hsiuchen; Polleux, Franck; Chan, David C.; Shaw, Reuben J.

doi:10.1126/science.aab4138

Cited by 899 publications

(909 citation statements)

References 41 publications

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“…Whether or not these effects can be neutralized by substrate supplementation or stimulation of fusion genes such as mitofusin (Mfn), or if pathological changes in mitochondrial dynamics may more generally be rescued by increased substrate delivery, are questions that should be considered for future studies. In this respect, it has recently been reported that cellular energy deficiency induces mitochondrial fission via AMPK-dependent Fis1 and Drp1 recruitment (33). This fission has been interpreted as being prerequisite for the removal of faulty mitochondria by mitophagy (33), but our findings offer the alternative possibility that mitochondrial fragmentation enhances glycolytic metabolite delivery to mitochondria and thus maintains ATP output during times of high energetic demand.…”

Section: Discussioncontrasting

confidence: 36%

Direct Substrate Delivery Into Mitochondrial Fission–Deficient Pancreatic Islets Rescues Insulin Secretion

et al. 2017

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In pancreatic b-cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion. Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein Drp1, we demonstrate in this study that mitochondrial fission is necessary for glucose-stimulated insulin secretion in mouse and human islets. We confirm that genetic silencing of Drp1 increases mitochondrial proton leak in MIN6 cells. However, our comprehensive analysis of pancreatic islet bioenergetics reveals that Drp1 does not control insulin secretion via its effect on proton leak but instead via modulation of glucose-fueled respiration. Notably, pyruvate fully rescues the impaired insulin secretion of fission-deficient b-cells, demonstrating that defective mitochondrial dynamics solely affect substrate supply upstream of oxidative phosphorylation. The present findings provide novel insights into how mitochondrial dysfunction may cause pancreatic b-cell failure. In addition, the results will stimulate new thinking in the intersecting fields of mitochondrial dynamics and bioenergetics, as treatment of defective dynamics in mitochondrial diseases appears to be possible by improving metabolism upstream of mitochondria.The development of type 2 diabetes is associated with mitochondrial dysfunction in pancreatic b-cells. b-Cells have developed highly coordinated mechanisms that link glucose sensing with metabolic signaling cascades that direct the secretion of sufficient insulin to maintain glucose homeostasis (1). The mechanism underlying glucose-stimulated insulin secretion (GSIS) from b-cells involves glucose uptake by specific glucose transporters followed by glucose catabolism through glycolysis yielding pyruvate, which in turn is further catabolized via the tricarboxylic acid cycle. Both glycolysis and tricarboxylic acid cycle turnover generate reducing power that is used by the mitochondrial respiratory chain to produce ATP through oxidative phosphorylation. The resultant increase in the cytosolic ATP/ADP ratio closes ATP-sensitive K + (K ATP ) channels, thus depolarizing the plasma membrane. Depolarization triggers opening of voltagegated Ca 2+ channels, and the influx of Ca 2+ ions consequently leads to exocytosis of insulin-containing granules from b-cells (2). This sequence of events illustrates that b-cell mitochondria exert strong control over GSIS (3), as mitochondrial energy-transducing processes dictate how fast and efficiently glucose is converted to ATP. Mitochondrial dysfunction impairs glucose-insulin secretion coupling and ultimately promotes b-cell apoptosis and death, one of the key features of type 2 diabetes (4).Mitochondria are dynamic organelles that are constantly remodeled through the opposing action of fission and fusion proteins (5). Until recently, the influence of mitochondrial dynamics over energy transduction has been underappreciated. The continuous changes in mitochondrial morphology are controlle...

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Section: Discussioncontrasting

confidence: 36%

Direct Substrate Delivery Into Mitochondrial Fission–Deficient Pancreatic Islets Rescues Insulin Secretion

et al. 2017

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“…We found that the administration of the uncouplers alone did not show a direct impact on the growth or gene expression of tumor cells. Mitochondrial energy metabolism is closely linked with cellular metabolism via mTOR and AMPK (36,49,50). We found that uncouplers combined with PD-1 blockade activate not only the AMPK but also the mTOR pathway.…”

Section: Discussionmentioning

confidence: 89%

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Chamoto

Chowdhury

Kumar

et al. 2017

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

340

287

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Although immunotherapy by PD-1 blockade has dramatically improved the survival rate of cancer patients, further improvement in efficacy is required to reduce the fraction of less sensitive patients. In mouse models of PD-1 blockade therapy, we found that tumor-reactive cytotoxic T lymphocytes (CTLs) in draining lymph nodes (DLNs) carry increased mitochondrial mass and more reactive oxygen species (ROS). We show that ROS generation by ROS precursors or indirectly by mitochondrial uncouplers synergized the tumoricidal activity of PD-1 blockade by expansion of effector/ memory CTLs in DLNs and within the tumor. These CTLs carry not only the activation of mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) but also an increment of their downstream transcription factors such as PPAR-gamma coactivator 1α (PGC-1α) and T-bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1α also synergized the PD-1 blockade therapy whereas none of above-mentioned chemicals alone had any effects on tumor growth. These findings will pave a way to developing novel combinatorial therapies with PD-1 blockade.PD-1 | cancer immunotherapy | mitochondria | immune metabolism | PGC-1α

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“…PTMs of the mitochondrial adaptor protein Mff also promote recruitment of Drp1 to the OMM. In mouse embryonic fibroblasts, cellular stress induced by inhibitors of the mitochondrial electron transport chain triggers AMP-kinasemediated phosphorylation of Mff at S155 and S172, culminating in recruitment of Drp1 and mitochondrial fission (Toyama et al, 2016).…”

Section: Post-translational Regulation Of Mitochondrial Fission and Fmentioning

confidence: 99%

Mitochondrial dynamics in neuronal injury, development and plasticity

Flippo

Strack

2017

Journal of Cell Science

209

126

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AMP-activated protein kinase mediates mitochondrial fission in response to energy stress

Cited by 899 publications

References 41 publications

Direct Substrate Delivery Into Mitochondrial Fission–Deficient Pancreatic Islets Rescues Insulin Secretion

Direct Substrate Delivery Into Mitochondrial Fission–Deficient Pancreatic Islets Rescues Insulin Secretion

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Mitochondrial dynamics in neuronal injury, development and plasticity

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