bims-mecmid Biomed News
on Membrane communication in mitochondrial dynamics
Issue of 2021‒12‒19
nine papers selected by
Mauricio Cardenas Rodriguez
University of Padova
  1. Cristae junction as a fundamental switchboard for mitochondrial ion signaling and bioenergetics.
  2. ZFP36 protects against oxygen-glucose deprivation/reoxygenation-induced mitochondrial fragmentation and neuronal apoptosis through inhibiting NOX4-DRP1 pathway.
  3. The role of mitochondrial dynamics in mtDNA maintenance.
  4. Inhibition of Mitochondrial Fission by Drp-1 Blockade by Short-Term Leptin and Mdivi-1 Treatment Improves White Adipose Tissue Abnormalities in Obesity and Diabetes.
  5. Altered cardiac mitochondrial dynamics and biogenesis in rat after short-term cocaine administration.
  6. A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic tau mouse model of Alzheimer disease.
  7. TRAP1 inhibits MIC60 ubiquitination to mitigate the injury of cardiomyocytes and protect mitochondria in extracellular acidosis.
  8. Genetically encoded biosensors for evaluating NAD+/NADH ratio in cytosolic and mitochondrial compartments.
  9. VDAC2 and the BCL-2 family of proteins.
  1. Cell Calcium. 2021 Dec 10. pii: S0143-4160(21)00171-8. [Epub ahead of print]101 102517
    Cristae junction as a fundamental switchboard for mitochondrial ion signaling and bioenergetics.
    Benjamin Gottschalk, Corina T Madreiter-Sokolowski, Wolfgang F Graier.
      OPA1 and MICU1 are both involved in the regulation of mitochondrial Ca2+ uptake and the stabilization of the cristae junction, which separates the inner mitochondrial membrane into the interboundary membrane and the cristae membrane. In this mini-review, we focus on the synergetic control of OPA1 and MICU1 on the cristae junction that serves as a fundamental regulator of multiple mitochondrial functions. In particular, we point to the critical role of an adaptive cristae junction permeability in mitochondrial Ca2+ signaling, spatial H+ gradients and mitochondrial membrane potential, metabolic activity, and apoptosis. These characteristics bear on a distinct localization of the oxidative phosphorylation machinery, the FoF1-ATPase, and mitochondrial Ca2+uniporter (MCU) within sections of the inner mitochondrial membrane isolated by the cristae junction and regulated by proteins like OPA1 and MICU1. We specifically focus on the impact of MICU1-regulated cristae junction on the activity and distribution of MCU within the complex ultrastructure of mitochondria.
    DOI:  https://doi.org/10.1016/j.ceca.2021.102517
  2. Brain Res Bull. 2021 Dec 09. pii: S0361-9230(21)00340-3. [Epub ahead of print]
    ZFP36 protects against oxygen-glucose deprivation/reoxygenation-induced mitochondrial fragmentation and neuronal apoptosis through inhibiting NOX4-DRP1 pathway.
    Hengjiang Guo, Yan Jiang, Zhiqing Gu, Lulu Ren, Change Zhu, Shenghua Yu, Rong Wei.
      The imbalance of mitochondrial dynamics plays an important role in the pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Zinc-finger protein 36 (ZFP36) has been documented to have neuroprotective effects, however, whether ZFP36 is involved in the regulation of neuronal survival during cerebral I/R injury remains unknown. In this study, we found that the transcriptional and translational levels of ZFP36 were increased in immortalized hippocampal HT22 neuronal cells after oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. ZFP36 gene silencing exacerbated OGD/R-induced dynamin-related protein 1 (DRP1) activity, mitochondrial fragmentation, oxidative stress and neuronal apoptosis, whereas ZFP36 overexpression exhibited the opposite effects. Besides, we found that NADPH oxidase 4 (NOX4) was upregulated by OGD/R, and NOX4 inhibition remarkably attenuated OGD/R-instigated DRP1 activity, mitochondrial fragmentation and neuronal apoptosis. Further study demonstrated that ZFP36 targeted NOX4 mRNA directly by binding to the AU-rich elements (AREs) in the NOX4 3'-untranslated regions (3'-UTR) and inhibited NOX4 expression. Taken together, our data indicate that ZFP36 protects against OGD/R-induced neuronal injury by inhibiting NOX4-mediated DRP1 activation and excessive mitochondrial fission. Pharmacological targeting of ZFP36 to suppress excessive mitochondrial fission may provide new therapeutic strategies in the treatment of cerebral I/R injury.
    Keywords:  DRP1; ZFP36; mitochondrial dysfunction; mitochondrial fission; neuronal apoptosis
    DOI:  https://doi.org/10.1016/j.brainresbull.2021.12.003
  3. J Cell Sci. 2021 Dec 15. pii: jcs258944. [Epub ahead of print]134(24):
    The role of mitochondrial dynamics in mtDNA maintenance.
    Rasha Sabouny, Timothy E Shutt.
      The dynamic nature of mitochondria, which can fuse, divide and move throughout the cell, allows these critical organelles to adapt their function in response to cellular demands, and is also important for regulating mitochondrial DNA (mtDNA). While it is established that impairments in mitochondrial fusion and fission impact the mitochondrial genome and can lead to mtDNA depletion, abnormal nucleoid organization or accumulation of deletions, it is not entirely clear how or why remodeling mitochondrial network morphology affects mtDNA. Here, we focus on recent advances in our understanding of how mitochondrial dynamics contribute to the regulation of mtDNA and discuss links to human disease.
    Keywords:  Fission; Fusion; Mitochondria; Mitochondrial dynamics; Mitophagy; mtDNA
    DOI:  https://doi.org/10.1242/jcs.258944
  4. Pharmacol Res. 2021 Dec 09. pii: S1043-6618(21)00612-5. [Epub ahead of print] 106028
    Inhibition of Mitochondrial Fission by Drp-1 Blockade by Short-Term Leptin and Mdivi-1 Treatment Improves White Adipose Tissue Abnormalities in Obesity and Diabetes.
    P Finocchietto, H Perez, G Blanco, Miksztowicz, C Marotte, C Morales, J Peralta, G Berg, C Poderoso, J J Poderoso, M C Carreras.
      BACKGROUND: Obesity and type 2 diabetes are chronic diseases characterized by insulin resistance, mitochondrial dysfunction and morphological abnormalities.OBJECTIVE: We have investigated if dysregulation of mitochondrial dynamics and biogenesis is involved in an animal model of obesity and diabetes.
    METHODS: The effect of short-term leptin and mdivi-1 -a selective inhibitor of Drp-1 fission-protein- treatment on mitochondrial dynamics and biogenesis was evaluated in epididymal white adipose tissue (WAT) from male ob/ob mice.
    RESULTS: An increase in Drp-1 protein levels and a decrease in Mfn2 and OPA-1 protein expression were observed with enhanced and sustained mitochondrial fragmentation in ob/ob mice compared to wt C57BL/6 animals (p<0.05). The content of mitochondrial DNA and PGC-1α mRNA expression -both parameters of mitochondrial biogenesis- were reduced in ob/ob mice (p<0.05). Treatment with leptin and mdivi-1 significantly increased mitochondrial biogenesis, improved fusion-to-fission balance and attenuated mitochondrial dysfunction, thus inducing white-to-beige adipocyte transdifferentiation. Measurements of glucose and lipid oxidation in adipocytes revealed that both leptin and mdivi-1 increase substrates oxidation while in vivo determination of blood glucose concentration showed decreased levels by 50% in ob/ob mice, almost to the wt level.
    CONCLUSIONS: Pharmacological targeting of Drp-1 fission protein may be a potential novel therapeutic tool for obesity and type 2 diabetes.
    Keywords:  Drp-1; biogenesis; dynamics; mdivi-1; mitochondria; white adipose tissue
    DOI:  https://doi.org/10.1016/j.phrs.2021.106028
  5. Sci Rep. 2021 Dec 16. 11(1): 24129
    Altered cardiac mitochondrial dynamics and biogenesis in rat after short-term cocaine administration.
    Shuheng Wen, Kana Unuma, Takeshi Funakoshi, Toshihiko Aki, Koichi Uemura.
      Abuse of the potent psychostimulant cocaine is widely established to have cardiovascular consequences. The cardiotoxicity of cocaine is mainly associated with oxidative stress and mitochondrial dysfunction. Mitochondrial dynamics and biogenesis, as well as the mitochondrial unfolded protein response (UPRmt), guarantee cardiac mitochondrial homeostasis. Collectively, these mechanisms act to protect against stress, injury, and the detrimental effects of chemicals on mitochondria. In this study, we examined the effects of cocaine on cardiac mitochondrial dynamics, biogenesis, and UPRmt in vivo. Rats administered cocaine via the tail vein at a dose of 20 mg/kg/day for 7 days showed no structural changes in the myocardium, but electron microscopy revealed a significant increase in the number of cardiac mitochondria. Correspondingly, the expressions of the mitochondrial fission gene and mitochondrial biogenesis were increased after cocaine administration. Significant increase in the expression and nuclear translocation of activating transcription factor 5, the major active regulator of UPRmt, were observed after cocaine administration. Accordingly, our findings show that before any structural changes are observable in the myocardium, cocaine alters mitochondrial dynamics, elevates mitochondrial biogenesis, and induces the activation of UPRmt. These alterations might reflect cardiac mitochondrial compensation to protect against the cardiotoxicity of cocaine.
    DOI:  https://doi.org/10.1038/s41598-021-03631-y
  6. Hum Mol Genet. 2021 Dec 17. pii: ddab360. [Epub ahead of print]
    A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic tau mouse model of Alzheimer disease.
    Ramesh Kandimalla, Maria Manczak, Jangampalli Adi Pradeepkiran, Hallie Morton, P Hemachandra Reddy.
      The purpose of our study is to understand the impact of a partial dynamin-related protein 1 (Drp1) on cognitive behavior, mitophagy, autophagy, and mitochondrial and synaptic activities in transgenic Tau mice in Alzheimer's disease (ad). Our lab reported increased levels of Aβ and P-Tau, and abnormal interactions between Aβ and Drp1, P-Tau, and Drp1 induced increased mitochondrial fragmentation and reduced fusion and synaptic activities in ad. These abnormal interactions, result in the proliferation of dysfunctional mitochondria in ad neurons. Recent research on mitochondria revealed that fission protein Drp1 is largely implicated in mitochondrial dynamics in ad. To determine the impact of reduced Drp1 in ad, we recently crossed transgenic Tau mice with Drp1 heterozygote knockout (Drp1+/-) mice and generated double mutant (P301LDrp1+/-) mice. In the current study, we assessed cognitive behavior, mRNA and protein levels of mitophagy, autophagy, mitochondrial biogenesis, dynamics and synaptic genes, mitochondrial morphology & mitochondrial function, dendritic spines in Tau mice relative to double mutant mice. When compared to Tau mice, double mutant mice did better on Morris Maze (reduced latency to find hidden platform, increased swimming speed and time spent on quadrant) and rotarod (stayed a longer period of time) tests. Both mRNA and proteins levels autophagy, mitophagy, mitochondrial biogenesis and synaptic proteins were increased in double mutant mice compared to Tau (P301L) mice. Dendritic spines were significantly increased; mitochondrial number is reduced and length is increased in double mutant mice. Based on these observations, we conclude that reduced Drp1 is beneficial in a symptomatic-transgenic Tau (P301L) mice.
    Keywords:  Mitochondria Alzheimer’s disease Mitophagy Autophagy Dynamin-related protein 1 Oxidative stress Mitochondrial biogenesis
    DOI:  https://doi.org/10.1093/hmg/ddab360
  7. Cell Death Discov. 2021 Dec 14. 7(1): 389
    TRAP1 inhibits MIC60 ubiquitination to mitigate the injury of cardiomyocytes and protect mitochondria in extracellular acidosis.
    Lingxiao Zhang, Ning Su, Yuanyuan Luo, Siyin Chen, Tongfeng Zhao.
      Extracellular acidosis-induced mitochondrial damage of cardiomyocytes leads to cardiac dysfunction, but no detailed mechanism or efficient therapeutic target has been reported. Here we found that the protein levels of MIC60 were decreased in H9C2 cells and heart tissues in extracellular acidosis, which caused mitochondrial damage and cardiac dysfunction. Overexpression of MIC60 maintains H9C2 cells viability, increases ATP production and mitochondrial membrane potential, mitigates the disruptions of mitochondrial structure and cardiac injury. Mechanistically, extracellular acidosis excessively promoted MIC60 ubiquitin-dependent degradation. TRAP1 mitigated acidosis-induced mitochondrial impairments and cardiac injury by directly interacting with MIC60 to decrease its ubiquitin-dependent degradation in extracellular acidosis.
    DOI:  https://doi.org/10.1038/s41420-021-00786-5
  8. Cell Rep Methods. 2021 Nov 22. pii: 100116. [Epub ahead of print]1(7):
    Genetically encoded biosensors for evaluating NAD+/NADH ratio in cytosolic and mitochondrial compartments.
    Qingxun Hu, Dan Wu, Matthew Walker, Pei Wang, Rong Tian, Wang Wang.
      The ratio of oxidized to reduced NAD (NAD+/NADH) sets intracellular redox balance and antioxidant capacity. Intracellular NAD is compartmentalized and the mitochondrial NAD+/NADH ratio is intricately linked to cellular function. Here, we report the monitoring of the NAD+/NADH ratio in mitochondrial and cytosolic compartments in live cells by using a modified genetic biosensor (SoNar). The fluorescence signal of SoNar targeted to mitochondria (mt-SoNar) or cytosol (ct-SoNar) responded linearly to physiological NAD+/NADH ratios in situ. NAD+/NADH ratios in cytosol versus mitochondria responded rapidly, but differently, to acute metabolic perturbations, indicating distinct NAD pools. Subcellular NAD redox balance regained homeostasis via communications through malate-aspartate shuttle. Mitochondrial and cytosolic NAD+/NADH ratios are influenced by NAD+ precursor levels and are distinctly regulated under pathophysiological conditions. Compartment-targeted biosensors and real-time imaging allow assessment of subcellular NAD+/NADH redox signaling in live cells, enabling future mechanistic research of NAD redox in cell biology and disease development.
    DOI:  https://doi.org/10.1016/j.crmeth.2021.100116
  9. Biochem Soc Trans. 2021 Dec 16. pii: BST20210753. [Epub ahead of print]
    VDAC2 and the BCL-2 family of proteins.
    Zheng Yuan, Grant Dewson, Peter E Czabotar, Richard W Birkinshaw.
      The BCL-2 protein family govern whether a cell dies or survives by controlling mitochondrial apoptosis. As dysregulation of mitochondrial apoptosis is a common feature of cancer cells, targeting protein-protein interactions within the BCL-2 protein family is a key strategy to seize control of apoptosis and provide favourable outcomes for cancer patients. Non-BCL-2 family proteins are emerging as novel regulators of apoptosis and are potential drug targets. Voltage dependent anion channel 2 (VDAC2) can regulate apoptosis. However, it is unclear how this occurs at the molecular level, with conflicting evidence in the literature for its role in regulating the BCL-2 effector proteins, BAK and BAX. Notably, VDAC2 is required for efficient BAX-mediated apoptosis, but conversely inhibits BAK-mediated apoptosis. This review focuses on the role of VDAC2 in apoptosis, discussing the current knowledge of the interaction between VDAC2 and BCL-2 family proteins and the recent development of an apoptosis inhibitor that targets the VDAC2-BAK interaction.
    Keywords:  BAK; BAX; BCL-2 family proteins; VDAC2; apoptosis; voltage-gated channels
    DOI:  https://doi.org/10.1042/BST20210753
This page is being maintained by Thomas Krichel. It was last updated on 2021‒12‒21 at 19:00:55.