bims-mitdyn 2021-09-19 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2021‒09‒19
seven papers selected by
Edmond Chan
Queen’s University, School of Medicine

Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination.
Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis.
Mitochondrial enzyme GPT2 regulates metabolic mechanisms required for neuron growth and motor function in vivo.
Dynamin-related protein 1 regulates substrate oxidation in skeletal muscle by stabilizing cellular and mitochondrial calcium dynamics.
Mitochondrial Abnormalities and Synaptic Damage in Huntington's Disease: a Focus on Defective Mitophagy and Mitochondria-Targeted Therapeutics.
PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism: Drp1-dependent mechanism.
Targeting Adaptive Cellular Responses To Mitochondrial Bioenergetic Deficiencies In Human Disease.

Elife. 2021 Sep 14. pii: e66278. [Epub ahead of print]10

Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination.

Gustavo Della Flora Nunes, Emma R Wilson, Edward Hurley, Bin He, Bert W O'Malley, Yannick Poitelon, Lawrence Wrabetz, M Laura Feltri.

  Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (PHB1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy in mice, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and c-Jun are continuously activated in the absence of Phb1, likely as part of the SC response to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and c-Jun may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria.

Keywords:  mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.66278
Cell Death Differ. 2021 Sep 12.

Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis.

Chang-Yong Choi, Mai Tram Vo, John Nicholas, Young Bong Choi.

Mitochondria support multiple cell functions, but an accumulation of dysfunctional or excessive mitochondria is detrimental to cells. We previously demonstrated that a defect in the autophagic removal of mitochondria, termed mitophagy, leads to the acceleration of apoptosis induced by herpesvirus productive infection. However, the exact molecular mechanisms underlying activation of mitophagy and regulation of apoptosis remain poorly understood despite the identification of various mitophagy-associated proteins. Here, we report that the mitochondrial translation elongation factor Tu, a mitophagy-associated protein encoded by the TUFM gene, locates in part on the outer membrane of mitochondria (OMM) where it acts as an inhibitor of altered mitochondria-induced apoptosis through its autophagic function. Inducible depletion of TUFM potentiated caspase-8-mediated apoptosis in virus-infected cells with accumulation of altered mitochondria. In addition, TUFM depletion promoted caspase-8 activation induced by treatment with TNF-related apoptosis-inducing ligand in cancer cells, potentially via dysregulation of mitochondrial dynamics and mitophagy. Importantly, we revealed the existence of and structural requirements for autophagy-competent TUFM on the OMM; the GxxxG motif within the N-terminal mitochondrial targeting sequences of TUFM was required for self-dimerization and mitophagy. Furthermore, we found that autophagy-competent TUFM was subject to ubiquitin-proteasome-mediated degradation but stabilized upon mitophagy or autophagy activation. Moreover, overexpression of autophagy-competent TUFM could inhibit caspase-8 activation. These studies extend our knowledge of mitophagy regulation of apoptosis and could provide a novel strategic basis for targeted therapy of cancer and viral diseases.

DOI: https://doi.org/10.1038/s41418-021-00868-y
Hum Mol Genet. 2021 Sep 14. pii: ddab269. [Epub ahead of print]

Mitochondrial enzyme GPT2 regulates metabolic mechanisms required for neuron growth and motor function in vivo.

Ozan Baytas, Shawn M Davidson, Ralph J DeBerardinis, Eric M Morrow.

The metabolic needs for postnatal growth of the human nervous system are vast. Recessive loss-of-function mutations in the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2) in humans cause postnatal undergrowth of brain, and cognitive and motor disability. We demonstrate that GPT2 governs critical metabolic mechanisms in neurons required for neuronal growth and survival. These metabolic processes include neuronal alanine synthesis and anaplerosis, the replenishment of tricarboxylic acid (TCA) cycle intermediates. We performed metabolomics across postnatal development in Gpt2-null mouse brain to identify the trajectory of dysregulated metabolic pathways: alterations in alanine occur earliest; followed by reduced TCA cycle intermediates and reduced pyruvate; followed by elevations in glycolytic intermediates and amino acids. Neuron-specific deletion of GPT2 in mice is sufficient to cause motor abnormalities and death pre-weaning, a phenotype identical to the germline Gpt2-null mouse. Alanine biosynthesis is profoundly impeded in Gpt2-null neurons. Exogenous alanine is necessary for Gpt2-null neuronal survival in vitro, but is not needed for Gpt2-null astrocytes. Dietary alanine supplementation in Gpt2-null mice enhances animal survival, and improves the metabolic profile of Gpt2-null brain, but does not alone appear to correct motor function. In surviving Gpt2-null animals, we observe smaller upper and lower motor neurons in vivo. We also observe selective death of lower motor neurons in vivo with worsening motor behavior with age. In conclusion, these studies of the pathophysiology of GPT2 Deficiency have identified metabolic mechanisms required for neuronal growth and that potentially underlie selective neuronal vulnerabilities in motor neurons.

DOI: https://doi.org/10.1093/hmg/ddab269
J Biol Chem. 2021 Sep 13. pii: S0021-9258(21)00998-4. [Epub ahead of print] 101196

Dynamin-related protein 1 regulates substrate oxidation in skeletal muscle by stabilizing cellular and mitochondrial calcium dynamics.

William T King, Christopher L Axelrod, Elizabeth R M Zunica, Robert C Noland, Gangarao Davuluri, Hisashi Fujioka, Bernard Tandler, Kathryn Pergola, Gerlinda E Hermann, Richard C Rogers, Sandra López-Domènech, Wagner S Dantas, Krisztian Stadler, Charles L Hoppel, John P Kirwan.

  Mitochondria undergo continuous cycles of fission and fusion to promote inheritance, regulate quality control, and mitigate organelle stress. More recently, this process of mitochondrial dynamics has been demonstrated to be highly sensitive to nutrient supply, ultimately conferring bioenergetic plasticity to the organelle. However, whether regulators of mitochondrial dynamics play a causative role in nutrient regulation remains unclear. In this study, we generated a cellular loss-of-function model for dynamin-related protein 1 (DRP1), the primary regulator of outer membrane mitochondrial fission. Loss of DRP1 (shDRP1) resulted in extensive ultrastructural and functional remodeling of mitochondria, characterized by pleomorphic enlargement, increased electron density of the matrix, and defective NADH and succinate oxidation. Despite increased mitochondrial size and volume, shDRP1 cells exhibited reduced cellular glucose uptake and mitochondrial fatty acid oxidation. Untargeted transcriptomic profiling revealed severe downregulation of genes required for cellular and mitochondrial calcium homeostasis, inhibition of ATP-stimulated calcium flux, and impaired substrate oxidation stimulated by calcium levels. The insights obtained herein suggest that DRP1 regulates fatty acid oxidation by altering whole-cell and mitochondrial calcium dynamics. These findings are relevant to the targetability of mitochondrial fission and have clinical relevance in the identification of treatments for fission-related pathologies such as hereditary neuropathies, inborn errors in metabolism, cancer, and chronic diseases.

Keywords:  calcium signaling; dynamin-related protein 1; mitochondrial dynamics; skeletal muscle; β-oxidation

DOI:  https://doi.org/10.1016/j.jbc.2021.101196
Mol Neurobiol. 2021 Sep 14.

Mitochondrial Abnormalities and Synaptic Damage in Huntington's Disease: a Focus on Defective Mitophagy and Mitochondria-Targeted Therapeutics.

Neha Sawant, Hallie Morton, Sudhir Kshirsagar, Arubala P Reddy, P Hemachandra Reddy.

  Huntington's disease (HD) is a fatal and pure genetic disease with a progressive loss of medium spiny neurons (MSN). HD is caused by expanded polyglutamine repeats in the exon 1 of HD gene. Clinically, HD is characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment, and emotional disturbances. Several years of intense research revealed that multiple cellular changes, including defective axonal transport, protein-protein interactions, defective bioenergetics, calcium dyshomeostasis, NMDAR activation, synaptic damage, mitochondrial abnormalities, and selective loss of medium spiny neurons are implicated in HD. Recent research on mutant huntingtin (mHtt) and mitochondria has found that mHtt interacts with the mitochondrial division protein, dynamin-related protein 1 (DRP1), enhances GTPase DRP1 enzymatic activity, and causes excessive mitochondrial fragmentation and abnormal distribution, leading to defective axonal transport of mitochondria and selective synaptic degeneration. Recent research also revealed that failure to remove dead and/or dying mitochondria is an early event in the disease progression. Currently, efforts are being made to reduce abnormal protein interactions and enhance synaptic mitophagy as therapeutic strategies for HD. The purpose of this article is to discuss recent research in HD progression. This article also discusses recent developments of cell and mouse models, cellular changes, mitochondrial abnormalities, DNA damage, bioenergetics, oxidative stress, mitophagy, and therapeutics strategies in HD.

Keywords:  Huntington’s disease; Mitochondria-targeted therapies; Mitochondrial abnormalities; Mitophagy; Mutant huntingtin; Polyglutamine repeat expansion

DOI:  https://doi.org/10.1007/s12035-021-02556-x
Mol Oncol. 2021 Sep 17.

PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism: Drp1-dependent mechanism.

Luca Simula, Ylenia Antonucci, Giorgia Scarpelli, Valeria Cancila, Alessandra Colamatteo, Simona Manni, Biagio De Angelis, Concetta Quintarelli, Claudio Procaccini, Giuseppe Matarese, Claudio Tripodo, Silvia Campello.

  Programmed cell death-1 (PD-1) signaling downregulates the T cell response, promoting an exhausted state in tumor-infiltrating T cells, through mostly unveiled molecular mechanisms. Dynamin-related protein-1 (Drp1)-dependent mitochondrial fission plays a crucial role in sustaining T cell motility, proliferation, survival, and glycolytic engagement. Interestingly, such processes are exactly those inhibited by PD-1 in tumor-infiltrating T cells. Here, we show that PD-1pos CD8+ T cells infiltrating an MC38 (murine adenocarcinoma)-derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared to PD-1neg counterparts. Also, PD-1pos lymphocytic elements infiltrating a human colon cancer rarely express active Drp1. Mechanistically, PD-1 signaling directly prevents mitochondria fragmentation following T cell stimulation by downregulating Drp1 phosphorylation on Ser616, via regulation of the ERK1/2 and mTOR pathways. In addition, downregulation of Drp1 activity in tumor-infiltrating PD-1pos CD8+ T cells seems to be a mechanism exploited by PD-1 signaling to reduce motility and proliferation of these cells. Overall, our data indicate that the modulation of Drp1 activity in tumor-infiltrating T cells may become a valuable target to ameliorate the anti-cancer immune response in future immunotherapy approaches.

Keywords:  Drp1; PD-1; T cell; mitochondria; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1002/1878-0261.13103
FEBS J. 2021 Sep 12.

Targeting Adaptive Cellular Responses To Mitochondrial Bioenergetic Deficiencies In Human Disease.

Christopher F Bennett, Conor T Ronayne, Pere Puigserver.

  Mitochondrial dysfunction is increasingly appreciated as a central contributor to human disease. Oxidative metabolism at the mitochondrial respiratory chain produces ATP and is intricately tied to redox homeostasis and biosynthetic pathways. Metabolic stress arising from genetic mutations in mitochondrial genes and environmental factors such as malnutrition or overnutrition is perceived by the cell and leads to adaptive and maladaptive responses that can underlie pathology. Here, we will outline cellular sensors that react to alterations in energy production, organellar redox, and metabolites stemming from mitochondrial disease (MD) mutations. MD is a heterogenous group of disorders primarily defined by defects in mitochondrial oxidative phosphorylation from nuclear or mitochondrial-encoded gene mutations. Pre-clinical therapies that improve fitness of MD mouse models have been recently identified. Targeting metabolic/energetic deficiencies, maladaptive signaling processes, and hyper-oxygenation of tissues are all strategies aside from direct genetic approaches that hold therapeutic promise. A further mechanistic understanding of these curative processes as well as the identification of novel targets will significantly impact mitochondrial biology and disease research.

Keywords:  Mitochondrial dysfunction; hypoxia; mTORC1; metabolism; mitochondrial disease; mitochondrial signaling; oxidative stress; reactive oxygen species; redox homeostasis

DOI:  https://doi.org/10.1111/febs.16195