Calcineurin Links Mitochondrial Elongation with Energy Metabolism

Pfluger, Paul T.; Kabra, Dhiraj G.; Aichler, Michaela; Schriever, Sonja C.; Pfuhlmann, Katrin; García, Verónica Casquero; Lehti, Maarit; Weber, Jon; Kutschke, Maria; Rozman, Jan; Elrod, John W.; Hevener, Andrea L.; Feuchtinger, Annette; Angelis, Martin Hrabé de; Walch, Axel; Rollmann, Stephanie M.; Aronow, Bruce J.; Müller, Timo; Pérez-Tilve, Diego; Jastroch, Martin; Luca, María De; Molkentin, Jeffery D.; Tschöp, Matthias H.

doi:10.1016/j.cmet.2015.08.022

Cited by 76 publications

(56 citation statements)

References 62 publications

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“…In fact, muscle-specific transgenic mice that overexpress an activated form of calcineurin show increased glycogen accumulation and lipid oxidation (Long et al., 2007) and upregulation of PGC1α, several glycolytic enzymes, mitochondrial genes, genes related to lipid metabolism, and GLUT4 (Long and Zierath, 2008). Conversely, muscle-specific calcineurin KO mice show exercise intolerance when subjected to exhausting physical activity (Pfluger et al., 2015). Finally, immunosuppression therapy by high-dose treatment with calcineurin inhibitors cylosporin A or tacrolimus (FK-506) has been associated with a higher risk for developing obesity and diabetes in patients (T D Correia et al., 2003).…”

Section: Discussionmentioning

confidence: 99%

Transcription Factor EB Controls Metabolic Flexibility during Exercise

et al. 2017

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SummaryThe transcription factor EB (TFEB) is an essential component of lysosomal biogenesis and autophagy for the adaptive response to food deprivation. To address the physiological function of TFEB in skeletal muscle, we have used muscle-specific gain- and loss-of-function approaches. Here, we show that TFEB controls metabolic flexibility in muscle during exercise and that this action is independent of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Indeed, TFEB translocates into the myonuclei during physical activity and regulates glucose uptake and glycogen content by controlling expression of glucose transporters, glycolytic enzymes, and pathways related to glucose homeostasis. In addition, TFEB induces the expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation. This coordinated action optimizes mitochondrial substrate utilization, thus enhancing ATP production and exercise capacity. These findings identify TFEB as a critical mediator of the beneficial effects of exercise on metabolism.

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Section: Discussionmentioning

confidence: 99%

Transcription Factor EB Controls Metabolic Flexibility during Exercise

et al. 2017

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“…For example, when Ca 2+ -buffering activity is altered in mitochondria, the cytosolic calcium level will increase and this eventually triggers calcineurin-mediated MT fission. Moreover, calcineurin deficient skeletal muscles in mice exhibit a highly elongated mitochondrial network and increased respiratory chain activity [54].…”

Section: Mitochondrial Fusion Maintain Metabolic Homeostasis During Nmentioning

confidence: 99%

Mitochondrial Dynamics in Basal and Stressful Conditions

Zemirli

Morel

Molino

2018

IJMS

136

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The historical role of mitochondria resides in converting the energy released during the oxidation of macromolecules (carbohydrates, lipids and proteins) into adenosine tri-phosphate, a major form of chemically stored energy which sustains cell growth and homeostasis. Beyond this role in bioenergetics regulation, mitochondria play a role in several other cellular processes including lipid metabolism, cellular calcium homeostasis, autophagy and immune responses. Furthermore, mitochondria are highly dynamic organelles: as all other cellular endomembranes, they are continuously moving along cytoskeleton, and, most importantly, they constantly interact one with each other by membrane tethering, fusion and fission. This review aims to highlight the tight correlation between the morphodynamics of mitochondria and their biological function(s), in physiological as well as stress conditions, in particular nutrient deprivation, pathogen attack and some human diseases. Finally, we emphasize some crosstalk between the fusion/fission machinery and the autophagy pathway to ending on some speculative hypothesis to inspire future research in the field.

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“…Under conditions of high cytosolic Ca 2+ , dephosphorylation of Drp1 at Ser-637 by calcineurin induces mitochondrial fission [51, 52, 61–63]. The ablation of calcineurin in skeletal muscle leads to Ser-637 hyperphosphorylation of Drp1 causing elongation of mitochondria into ‘power-cable’-shaped filaments and increased mitochondrial respiration [64]. In hyperglycemic conditions, O-GlcNAcylation of OPA1 [65] and Drp1 [56] causes dephosphorylation of Ser-637 and the translocation of Drp1 to the OMM.…”

Section: Mitochondrial Fission Proteinsmentioning

confidence: 99%

Mitochondrial-Shaping Proteins in Cardiac Health and Disease – the Long and the Short of It!

Ong

Kalkhoran

Hernández‐Reséndiz

et al. 2017

Cardiovasc Drugs Ther

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Mitochondrial health is critically dependent on the ability of mitochondria to undergo changes in mitochondrial morphology, a process which is regulated by mitochondrial shaping proteins. Mitochondria undergo fission to generate fragmented discrete organelles, a process which is mediated by the mitochondrial fission proteins (Drp1, hFIS1, Mff and MiD49/51), and is required for cell division, and to remove damaged mitochondria by mitophagy. Mitochondria undergo fusion to form elongated interconnected networks, a process which is orchestrated by the mitochondrial fusion proteins (Mfn1, Mfn2 and OPA1), and which enables the replenishment of damaged mitochondrial DNA. In the adult heart, mitochondria are relatively static, are constrained in their movement, and are characteristically arranged into 3 distinct subpopulations based on their locality and function (subsarcolemmal, myofibrillar, and perinuclear). Although the mitochondria are arranged differently, emerging data supports a role for the mitochondrial shaping proteins in cardiac health and disease. Interestingly, in the adult heart, it appears that the pleiotropic effects of the mitochondrial fusion proteins, Mfn2 (endoplasmic reticulum-tethering, mitophagy) and OPA1 (cristae remodeling, regulation of apoptosis, and energy production) may play more important roles than their pro-fusion effects. In this review article, we provide an overview of the mitochondrial fusion and fission proteins in the adult heart, and highlight their roles as novel therapeutic targets for treating cardiac disease.

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Calcineurin Links Mitochondrial Elongation with Energy Metabolism

Cited by 76 publications

References 62 publications

Transcription Factor EB Controls Metabolic Flexibility during Exercise

Transcription Factor EB Controls Metabolic Flexibility during Exercise

Mitochondrial Dynamics in Basal and Stressful Conditions

Mitochondrial-Shaping Proteins in Cardiac Health and Disease – the Long and the Short of It!

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