bims-mecmid Biomed News
on Membrane communication in mitochondrial dynamics
Issue of 2022–04–03
six papers selected by
Mauricio Cardenas Rodriguez, University of Padova
  1. Mitochondrial Protein Translocation Machinery: From TOM Structural Biogenesis to Functional Regulation.
  2. Mitochondrial Fission and Fusion in Tumor Progression to Metastasis.
  3. Pharmacological Targeting of Mitochondrial Fission and Fusion Alleviates Cognitive Impairment and Brain Pathologies in Pre-diabetic Rats.
  4. Effects of Mitochondrial Dynamics in the Pathophysiology of Obesity.
  5. Chronic exposition to ozone induces cardiac antioxidant response and overexpression of either mitochondrial fision protein DRP1 and hipertrophyc-related proteins.
  6. Mitochondrial dynamics and biogenesis indicators may serve as potential biomarkers for diagnosis of myasthenia gravis.
  1. J Biol Chem. 2022 Mar 25. pii: S0021-9258(22)00310-6. [Epub ahead of print] 101870
    Mitochondrial Protein Translocation Machinery: From TOM Structural Biogenesis to Functional Regulation.
    Ulfat Mohd Hanif Sayyed, Radhakrishnan Mahalakshmi.
      The human mitochondrial outer membrane is biophysically unique as it is the only membrane possessing transmembrane β-barrel proteins (mitochondrial outer membrane proteins, mOMPs) in the cell. The most vital of the three mOMPs is the core protein of the translocase of the outer mitochondrial membrane (TOM) complex. Identified first as MOM38 in Neurospora in 1990, the structure of Tom40, the core 19-stranded β-barrel translocation channel, was solved in 2017, after nearly three decades. Remarkably, the past four years have witnessed an exponential increase in structural and functional studies of yeast and human TOM complexes. In addition to being conserved across all eukaryotes, the TOM complex is the sole ATP-independent import machinery for nearly all of the ∼1000-1500 known mitochondrial proteins. Recent cryo-EM structures have provided detailed insight into both possible assembly mechanisms of the TOM core complex and organizational dynamics of the import machinery, and now reveal novel regulatory interplay with other mOMPs. Functional characterization of the TOM complex using biochemical and structural approaches has also revealed mechanisms for substrate recognition and at least five defined import pathways for precursor proteins. In this review, we discuss the discovery, recently solved structures, molecular function, and regulation of the TOM complex and its constituents, along with the implications these advances have for human diseases.
    Keywords:  TOM complex; Tom40; dysregulation; mitochondrial outer membrane; protein import pathways; transmembrane β-barrels
    DOI:  https://doi.org/10.1016/j.jbc.2022.101870
  2. Front Cell Dev Biol. 2022 ;10 849962
    Mitochondrial Fission and Fusion in Tumor Progression to Metastasis.
    Dillon P Boulton, M Cecilia Caino.
      Mitochondria are highly dynamic organelles which can change their shape, via processes termed fission and fusion, in order to adapt to different environmental and developmental contexts. Due to the importance of these processes in maintaining a physiologically healthy pool of mitochondria, aberrant cycles of fission/fusion are often seen in pathological contexts. In this review we will discuss how dysregulated fission and fusion promote tumor progression. We focus on the molecular mechanisms involved in fission and fusion, discussing how altered mitochondrial fission and fusion change tumor cell growth, metabolism, motility, and invasion and, finally how changes to these tumor-cell intrinsic phenotypes directly and indirectly impact tumor progression to metastasis. Although this is an emerging field of investigation, the current consensus is that mitochondrial fission positively influences metastatic potential in a broad variety of tumor types. As mitochondria are now being investigated as vulnerable targets in a variety of cancer types, we underscore the importance of their dynamic nature in potentiating tumor progression.
    Keywords:  cancer; fission; fusion; metastasis; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.3389/fcell.2022.849962
  3. Mol Neurobiol. 2022 Apr 02.
    Pharmacological Targeting of Mitochondrial Fission and Fusion Alleviates Cognitive Impairment and Brain Pathologies in Pre-diabetic Rats.
    Chayodom Maneechote, Titikorn Chunchai, Nattayaporn Apaijai, Nipon Chattipakorn, Siriporn C Chattipakorn.
      It has recently been accepted that long-term high-fat diet (HFD) intake is a significant possible cause for prediabetes and cognitive and brain dysfunction through the disruption of brain mitochondrial function and dynamic balance. Although modulation of mitochondrial dynamics by inhibiting fission and promoting fusion has been shown to reduce the morbidity and mortality associated with a variety of chronic diseases, the impact of either pharmacological inhibition of mitochondrial fission (Mdivi-1) or stimulation of fusion (M1) on brain function in HFD-induced prediabetic models has never been studied. Thirty-two male Wistar rats were separated into 2 groups and fed either a normal diet (ND, n = 8) or HFD (n = 24) for 14 weeks. At week 12, HFD-fed rats were divided into 3 subgroups (n = 8/subgroup) and given an intraperitoneal injection of either saline, Mdivi-1 (1.2 mg/kg/day), or M1 (2 mg/kg/day) for 2 weeks. Cognitive function and metabolic parameters were determined toward the end of the protocol. The rats then were euthanized, and the brain was immediately removed in order to evaluate brain mitochondrial function and mitochondrial dynamics. HFD-fed rats experienced prediabetes, evidenced by elevated plasma insulin and the HOMA index, impaired mitochondrial function in the brain, altered dynamic regulation, and cognitive impairment were also found. Mdivi-1 and M1 treatment exerted neuroprotection to a similar extent by improving metabolic parameters, balancing mitochondrial dynamics, and reducing mitochondrial dysfunction, resulting in a gradual increase in cognitive function. Therefore, pharmacological targeting of mitochondrial fission and fusion protected the brain against chronic HFD-induced prediabetes.
    Keywords:  Brain; Cognition; Mitochondria; Mitochondrial dynamics; Obesity; Prediabetes
    DOI:  https://doi.org/10.1007/s12035-022-02813-7
  4. Front Biosci (Landmark Ed). 2022 Mar 18. 27(3): 107
    Effects of Mitochondrial Dynamics in the Pathophysiology of Obesity.
    Jinling Wang, Xiufu Lin, Ningning Zhao, Guanping Dong, Wei Wu, Ke Huang, Junfen Fu.
      Obesity has become an urgent and serious public health challenge with an overwhelming increase over the decades worldwide. The rate of obese children and adolescents has recently accelerated, especially in China. Obesity is closely related to unbalanced cellular energy metabolism. Mitochondria, as the main organelles of energy metabolism, play an important role in the pathophysiology of obesity. Recent researches have revealed that mitochondrial dynamics with constant fission and fusion, can alter mitochondrial structure, organelle connections, ROS production, neuronal activity, and OXPHOS system as well as adipose tissue thermogenesis, which ultimately lead to obesity. In this review, we will update the latest findings about mitochondrial fission/fusion related GTPase proteins and discuss the effects of mitochondrial dynamics in the pathophysiology of obesity.
    Keywords:  Drp1; Mfn1; Mfn2; Opa1; fission; fusion; mitochondrial dynamics; obesity
    DOI:  https://doi.org/10.31083/j.fbl2703107
  5. J Bioenerg Biomembr. 2022 Mar 26.
    Chronic exposition to ozone induces cardiac antioxidant response and overexpression of either mitochondrial fision protein DRP1 and hipertrophyc-related proteins.
    Nancy P Gómez-Crisóstomo, Selva Rivas-Arancibia, Erika Rodríguez-Martínez, Erick N De la Cruz-Hernández, Corazón de María Márquez Álvarez, Pablo Alexis Estrada Caraveo, Noemí Gelista Herrera, Marlen Valdés-Fuentes, Eduardo Martínez-Abundis.
      Pollution is considered a risk factor for cardiovascular disease; however, the mechanisms to explain this relationship are not well understood; ozone is one of the most abundant and studied air contaminants. Our study aimed to evaluate the effect of chronic exposition of rats to controlled low doses of ozone on oxidative stress, apoptosis, mitochondrial dynamics, and cardiac hypertrophy. Male Wistar rats were daily exposed to low ozone doses during 7, 15, 30, and 60 days, 4 h/day. Hearts were dissected, and homogenates were prepared. Oxidative stress was evaluated by TBARS and protein nitrosylation in addition to Superoxide dismutase 1 (SOD1) and Catalase levels; the apoptosis related-proteins caspase 3, caspase 9, Bax, Bcl-2, and the mitochondrial dynamic-associated proteins Fis1, Drp1, OPA1, and Mfn1 were quantified by western blot among the cardiac hypertrophy indicator alpha-actin (cardiac actin). There were no changes in the oxidative stress markers, however SOD1 expression increases. Caspase 3 expression decreased, whereas caspase 9 increased without changes in Bax or Bcl-2. Mitochondrial fission may be favored according to the increased expression of Drp1 but not changes in fusion-related proteins OPA1 and Mfn1. Finally, the molecular marker for cardiac hypertrophy was overexpressed after 30 and 60 days of ozone exposition. The chronic exposition to ozone induces a deleterious effect on cardiac mitochondria. Antioxidant defenses also show changes in relation to exposure time, as well as an apparent pro-hypertrophic effect associated with altered mitochondrial dynamics.
    Keywords:  Cardiac hypertrophy; Mitochondrial dynamics; Oxidative stress; Ozone toxicity; Pollution
    DOI:  https://doi.org/10.1007/s10863-022-09937-4
  6. Exp Ther Med. 2022 Apr;23(4): 307
    Mitochondrial dynamics and biogenesis indicators may serve as potential biomarkers for diagnosis of myasthenia gravis.
    Lanqi Li, Donghong Cai, Huiya Zhong, Fengbin Liu, Qilong Jiang, Jian Liang, Peiwu Li, Yafang Song, Aidong Ji, Wei Jiao, Jingwei Song, Jinqiu Li, Zhiwei Chen, Qing Li, Lingling Ke.
      Due to challenges in diagnosing myasthenia gravis (MG), identifying novel diagnostic biomarkers for this disease is essential. Mitochondria are key organelles that regulate multiple physiological functions, such as energy production, cell proliferation and cell death. In the present study, Mfn1/2, Opa1, Drp1, Fis1, AMPK, PGC-1α, NRF-1 and TFAM were compared between patients with MG and healthy subjects to identify potential diagnostic biomarkers for MG. Blood samples were collected from 50 patients with MG and 50 healthy subjects. The participants' demographic information and routine blood test results were recorded. Mitochondrial dynamics were evaluated and levels of Mfn1/2, Opa1, Drp1, Fis1, AMPK, PGC-1α, NRF-1 and TFAM were determined in peripheral blood mononuclear cells using western blotting and reverse transcription-quantitative PCR, respectively. Receiver operating characteristic curve analysis was used to evaluate the diagnostic accuracy of these indicators. The areas under the curve values of Mfn1/2, Opa1, Drp1, Fis1,AMPK, PGC-1α, NRF-1 and TFAM were 0.5408-0.8696. Compared with control subjects, mRNA expression levels of Mfn1/2, Opa1, AMPK, PGC-1α, NRF-1 and TFAM were lower, while those of Drp1 and Fis1 were higher in patients with MG. The protein expression levels of all these molecules were lower in patients with MG than in control subjects. These results suggested that mitochondrial dynamics and biogenesis indicators may be diagnostic biomarkers for MG.
    Keywords:  biogenesis; biomarkers; mitochondrial dynamics; myasthenia gravis; peripheral blood mononuclear cells
    DOI:  https://doi.org/10.3892/etm.2022.11236
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