bims-mitper Biomed News
on Mitochondrial Permeabilization
Issue of 2023‒04‒30
five papers selected by
Bradley Irizarry
Thomas Jefferson University

  1. Clin Chem. 2023 Apr 26. pii: hvad037. [Epub ahead of print]
      BACKGROUND: Mitochondria are cytosolic organelles within most eukaryotic cells. Mitochondria generate the majority of cellular energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation (OxPhos). Pathogenic variants in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) lead to defects in OxPhos and physiological malfunctions (Nat Rev Dis Primer 2016;2:16080.). Patients with primary mitochondrial disorders (PMD) experience heterogeneous symptoms, typically in multiple organ systems, depending on the tissues affected by mitochondrial dysfunction. Because of this heterogeneity, clinical diagnosis is challenging (Annu Rev Genomics Hum Genet 2017;18:257-75.). Laboratory diagnosis of mitochondrial disease depends on a multipronged analysis that can include biochemical, histopathologic, and genetic testing. Each of these modalities has complementary strengths and limitations in diagnostic utility.CONTENT: The primary focus of this review is on diagnosis and testing strategies for primary mitochondrial diseases. We review tissue samples utilized for testing, metabolic signatures, histologic findings, and molecular testing approaches. We conclude with future perspectives on mitochondrial testing.
    SUMMARY: This review offers an overview of the current biochemical, histologic, and genetic approaches available for mitochondrial testing. For each we review their diagnostic utility including complementary strengths and weaknesses. We identify gaps in current testing and possible future avenues for test development.
  2. Nat Aging. 2023 Apr 17.
      Chronic systemic inflammation is one of the hallmarks of the aging immune system. Here we show that activated T cells from older adults contribute to inflammaging by releasing mitochondrial DNA (mtDNA) into their environment due to an increased expression of the cytokine-inducible SH2-containing protein (CISH). CISH targets ATP6V1A, an essential component of the proton pump V-ATPase, for proteasomal degradation, thereby impairing lysosomal function. Impaired lysosomal activity caused intracellular accumulation of multivesicular bodies and amphisomes and the export of their cargos, including mtDNA. CISH silencing in T cells from older adults restored lysosomal activity and prevented amphisomal release. In antigen-specific responses in vivo, CISH-deficient CD4+ T cells released less mtDNA and induced fewer inflammatory cytokines. Attenuating CISH expression may present a promising strategy to reduce inflammation in an immune response of older individuals.
  3. Adv Drug Deliv Rev. 2023 Apr 21. pii: S0169-409X(23)00156-4. [Epub ahead of print] 114841
      Neurodegenerative diseases (NDs) are progressive disorders that cause the degeneration of neurons. Mitochondrial dysfunction is a common symptom in NDs and plays a crucial role in neuronal loss. Mitochondrial abnormalities can be observed in the early stages of NDs and evolve throughout disease progression. Visualizing mitochondrial abnormalities can help understand ND progression and develop new therapeutic strategies. Fluorescence microscopy is a powerful tool for dynamically imaging mitochondria due to its high sensitivity and spatiotemporal resolution. This review discusses the relationship between mitochondrial dysfunction and ND progression, potential biomarkers for imaging dysfunctional mitochondria, advances in fluorescence microscopy for detecting organelles, the performance of fluorescence probes in visualizing ND-associated mitochondria, and the challenges and opportunities for developing new generations of fluorescence imaging platforms for monitoring mitochondria in NDs.
    Keywords:  Fluorescence microscopic imaging; Fluorescence probes; Mitochondria dysfunction; Neurodegenerative diseases
  4. Neuron. 2023 Apr 24. pii: S0896-6273(23)00263-5. [Epub ahead of print]
      Corticosteroid-mediated stress responses require the activation of complex brain circuits involving mitochondrial activity, but the underlying cellular and molecular mechanisms are scantly known. The endocannabinoid system is implicated in stress coping, and it can directly regulate brain mitochondrial functions via type 1 cannabinoid (CB1) receptors associated with mitochondrial membranes (mtCB1). In this study, we show that the impairing effect of corticosterone in the novel object recognition (NOR) task in mice requires mtCB1 receptors and the regulation of mitochondrial calcium levels in neurons. Different brain circuits are modulated by this mechanism to mediate the impact of corticosterone during specific phases of the task. Thus, whereas corticosterone recruits mtCB1 receptors in noradrenergic neurons to impair NOR consolidation, mtCB1 receptors in local hippocampal GABAergic interneurons are required to inhibit NOR retrieval. These data reveal unforeseen mechanisms mediating the effects of corticosteroids during different phases of NOR, involving mitochondrial calcium alterations in different brain circuits.
    Keywords:  GABA; consolidation; corticosterone; endocannabinoids; hippocampus; locus coeruleus; mitochondrial CB(1) receptor; mitochondrial calcium; noradrenaline; object recognition memory; retrieval