bims-mecmid 2022-04-24 papers

Neurobiol Dis. 2022 Apr 19. pii: S0969-9961(22)00129-2. [Epub ahead of print] 105737

SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-β oligomers.

Andrés Norambuena, Xuehan Sun, Horst Wallrabe, Ruofan Cao, Naidi Sun, Evelyn Pardo, Nutan Shivange, Dora Bigler Wang, Lisa A Post, Heather A Ferris, Song Hu, Ammasi Periasamy, George S Bloom.

Altered mitochondrial DNA (mtDNA) occurs in neurodegenerative disorders like Alzheimer's disease (AD); how mtDNA synthesis is linked to neurodegeneration is poorly understood. We previously discovered Nutrient-induced Mitochondrial Activity (NiMA), an inter-organelle signaling pathway where nutrient-stimulated lysosomal mTORC1 activity regulates mtDNA replication in neurons by a mechanism sensitive to amyloid-β oligomers (AβOs), a primary factor in AD pathogenesis (Norambuena et al., 2018). Using 5-ethynyl-2'-deoxyuridine (EdU) incorporation into mtDNA of cultured neurons, along with photoacoustic and mitochondrial metabolic imaging of cultured neurons and mouse brains, we show these effects being mediated by mTORC1-catalyzed T40 phosphorylation of superoxide dismutase 1 (SOD1). Mechanistically, tau, another key factor in AD pathogenesis and other tauopathies, reduced the lysosomal content of the tuberous sclerosis complex (TSC), thereby increasing NiMA and suppressing SOD1 activity and mtDNA synthesis. AβOs inhibited these actions. Dysregulation of mtDNA synthesis was observed in fibroblasts derived from tuberous sclerosis (TS) patients, who lack functional TSC and elevated SOD1 activity was also observed in human AD brain. Together, these findings imply that tau and SOD1 couple nutrient availability to mtDNA replication, linking mitochondrial dysfunction to AD.

Keywords: Alzheimer's disease; Amino acids; Insulin; Tau; mTOR

DOI: https://doi.org/10.1016/j.nbd.2022.105737

Physiol Rep. 2022 Apr;10(8): e15281

Mitochondrial fusion- and fission-related protein expression in the regulation of skeletal muscle mass.

Daiki Nakano, Shuichi Machida.

Mitochondria in the skeletal muscle are essential for maintaining metabolic plasticity and function. Mitochondrial quality control encompasses the dynamics of the biogenesis and remodeling of mitochondria, characterized by the constant fission and fusion of mitochondria in response to metabolic stressors. However, the roles of mitochondrial fission or fusion in muscle hypertrophy and atrophy remain unclear. The aim of this study was to determine whether mitochondrial fusion and fission events are influenced by muscle hypertrophy or atrophy stimulation. Twenty-six male F344 rats were randomly assigned to a control group or were subjected to up to 14 days of either plantaris overload (via tenotomy of the gastrocnemius and soleus muscles; hypertrophy group) or hindlimb cast immobilization (atrophy group). After 14 days of treatment, plantaris muscle samples were collected to determine the expression levels of mitochondrial fusion- and fission-related proteins. Muscle weight and total muscle protein content increased following plantaris overload in the hypertrophy group, but decreased following immobilization for 14 days in the atrophy group. In the hypertrophied muscle, the level of activated dynamin-related protein 1 (Drp1), phosphorylated at Ser616, significantly increased by 25.8% (p = 0.014). Moreover, the protein expression level of mitochondrial fission factor significantly decreased by 36.5% in the hypertrophy group compared with that of the control group (p = 0.017). In contrast, total Drp1 level significantly decreased in the atrophied plantaris muscle (p = 0.011). Our data suggest that mitochondrial fission events may be influenced by both muscle hypertrophy and atrophy stimulation, and that mitochondrial fission- related protein Drp1 plays an important role in the regulation of skeletal muscle in response to mechanical stimulation.

Keywords: Drp1; atrophy; hypertrophy; mitochondrial quality control

DOI: https://doi.org/10.14814/phy2.15281

Front Immunol. 2022 ;13 873834

Impact of Drp1-Mediated Mitochondrial Dynamics on T Cell Immune Modulation.

Jun Song, Xiaofang Yi, Ruolin Gao, Li Sun, Zhixuan Wu, Shuling Zhang, Letian Huang, Chengbo Han, Jietao Ma.

In recent years, various breakthroughs have been made in tumor immunotherapy that have contributed to prolonging the survival of tumor patients. However, only a subset of patients respond to immunotherapy, which limits its use. One reason for this is that the tumor microenvironment (TME) hinders the migration and infiltration of T cells and affects their continuous functioning, resulting in an exhausted phenotype. Therefore, clarifying the mechanism by which T cells become exhausted is of significance for improving the efficacy of immunotherapy. Several recent studies have shown that mitochondrial dynamics play an important role in the immune surveillance function of T cells. Dynamin-related protein 1 (Drp1) is a key protein that mediates mitochondrial fission and maintains the mitochondrial dynamic network. Drp1 regulates various activities of T cells in vivo by mediating the activation of a series of pathways. In addition, abnormal mitochondrial dynamics were observed in exhausted T cells in the TME. As a potential target for immunotherapy, in this review, we describe in detail how Drp1 regulates various physiological functions of T cells and induces changes in mitochondrial dynamics in the TME, providing a theoretical basis for further research.

Keywords: T cell exhaustion; dynamin-related protein 1; immunotherapy; mitochondrial dynamics; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2022.873834

Dev Cell. 2022 Apr 14. pii: S1534-5807(22)00229-5. [Epub ahead of print]

Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage.

Kai Cao, Joel S Riley, Rosalie Heilig, Alfredo E Montes-Gómez, Esmee Vringer, Kevin Berthenet, Catherine Cloix, Yassmin Elmasry, David G Spiller, Gabriel Ichim, Kirsteen J Campbell, Andrew P Gilmore, Stephen W G Tait.

Mitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer is poorly understood. We find that mitochondrial dysfunction promotes DNA damage under conditions of increased apoptotic priming. Underlying this process, we reveal a key role for mitochondrial dynamics in the regulation of DNA damage and genome instability. The ability of mitochondrial dynamics to regulate oncogenic DNA damage centers upon the control of minority mitochondrial outer membrane permeabilization (MOMP), a process that enables non-lethal caspase activation leading to DNA damage. Mitochondrial fusion suppresses minority MOMP and its associated DNA damage by enabling homogeneous mitochondrial expression of anti-apoptotic BCL-2 proteins. Finally, we find that mitochondrial dysfunction inhibits pro-apoptotic BAX retrotranslocation, causing BAX mitochondrial localization and thereby promoting minority MOMP. Unexpectedly, these data reveal oncogenic effects of mitochondrial dysfunction that are mediated via mitochondrial dynamics and caspase-dependent DNA damage.

Keywords: DNA damage; MOMP; apoptosis; cancer; caspase; cell death; fission; fusion; mitochondrial dynamics

DOI: https://doi.org/10.1016/j.devcel.2022.03.019