bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2021‒05‒09
eight papers selected by
Avinash N. Mukkala
University of Toronto

  1. Nature. 2021 May 05.
      Mitochondrial fission is a highly regulated process that, when disrupted, can alter metabolism, proliferation and apoptosis1-3. Dysregulation has been linked to neurodegeneration3,4, cardiovascular disease3 and cancer5. Key components of the fission machinery include the endoplasmic reticulum6 and actin7, which initiate constriction before dynamin-related protein 1 (DRP1)8 binds to the outer mitochondrial membrane via adaptor proteins9-11, to drive scission12. In the mitochondrial life cycle, fission enables both biogenesis of new mitochondria and clearance of dysfunctional mitochondria through mitophagy1,13. Current models of fission regulation cannot explain how those dual fates are decided. However, uncovering fate determinants is challenging, as fission is unpredictable, and mitochondrial morphology is heterogeneous, with ultrastructural features that are below the diffraction limit. Here, we used live-cell structured illumination microscopy to capture mitochondrial dynamics. By analysing hundreds of fissions in African green monkey Cos-7 cells and mouse cardiomyocytes, we discovered two functionally and mechanistically distinct types of fission. Division at the periphery enables damaged material to be shed into smaller mitochondria destined for mitophagy, whereas division at the midzone leads to the proliferation of mitochondria. Both types are mediated by DRP1, but endoplasmic reticulum- and actin-mediated pre-constriction and the adaptor MFF govern only midzone fission. Peripheral fission is preceded by lysosomal contact and is regulated by the mitochondrial outer membrane protein FIS1. These distinct molecular mechanisms explain how cells independently regulate fission, leading to distinct mitochondrial fates.
  2. Cell Rep. 2021 May 04. pii: S2211-1247(21)00420-4. [Epub ahead of print]35(5): 109087
      Parvalbumin (PV) is a cytosolic Ca2+-binding protein highly expressed in fast skeletal muscle, contributing to an increased relaxation rate. Moreover, PV is an "atrogene" downregulated in most muscle atrophy conditions. Here, we exploit mice lacking PV to explore the link between the two PV functions. Surprisingly, PV ablation partially counteracts muscle loss after denervation. Furthermore, acute PV downregulation is accompanied by hypertrophy and upregulation by atrophy. PV ablation has a minor impact on sarcoplasmic reticulum but is associated with increased mitochondrial Ca2+ uptake, mitochondrial size and number, and contacts with Ca2+ release sites. Mitochondrial calcium uniporter (MCU) silencing abolishes the hypertrophic effect of PV ablation, suggesting that mitochondrial Ca2+ uptake is required for hypertrophy. In turn, an increase of mitochondrial Ca2+ is required to enhance expression of the pro-hypertrophy gene PGC-1α4, whose silencing blocks hypertrophy due to PV ablation. These results reveal how PV links cytosolic Ca2+ control to mitochondrial adaptations, leading to muscle mass regulation.
    Keywords:  calcium buffer; mitochondria; skeletal muscle
  3. Genetics. 2019 Aug 01. 212(4): 1429-1443
      Mitochondrial DNA (mtDNA) mutations cause severe congenital diseases but may also be associated with healthy aging. mtDNA is stochastically replicated and degraded, and exists within organelles which undergo dynamic fusion and fission. The role of the resulting mitochondrial networks in the time evolution of the cellular proportion of mutated mtDNA molecules (heteroplasmy), and cell-to-cell variability in heteroplasmy (heteroplasmy variance), remains incompletely understood. Heteroplasmy variance is particularly important since it modulates the number of pathological cells in a tissue. Here, we provide the first wide-reaching theoretical framework which bridges mitochondrial network and genetic states. We show that, under a range of conditions, the (genetic) rate of increase in heteroplasmy variance and de novo mutation are proportionally modulated by the (physical) fraction of unfused mitochondria, independently of the absolute fission-fusion rate. In the context of selective fusion, we show that intermediate fusion:fission ratios are optimal for the clearance of mtDNA mutants. Our findings imply that modulating network state, mitophagy rate, and copy number to slow down heteroplasmy dynamics when mean heteroplasmy is low could have therapeutic advantages for mitochondrial disease and healthy aging.
    Keywords:  cellular noise; heteroplasmy variance; mitochondrial DNA; mitochondrial networks
  4. FASEB J. 2021 Jun;35(6): e21586
      Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Only 10% of all cases are familial form, the remaining 90% are sporadic form with unknown genetic background. The etiology of sporadic AD is still not fully understood. Pathogenesis and pathobiology of this disease are limited due to the limited number of experimental models. We used primary culture of fibroblasts derived from patients diagnosed with sporadic form of AD for investigation of dynamic properties of mitochondria, including fission-fusion process and localization of mitochondria within the cell. We observed differences in mitochondrial network organization with decreased mitochondrial transport velocity, and a drop in the frequency of fusion-fission events. These studies show how mitochondrial dynamics adapt to the conditions of long-term mitochondrial stress that prevails in cells of sporadic form of AD.
    Keywords:  Alzheimer’s disease; fibroblasts; mitochondrial dynamics
  5. Cell Rep. 2021 May 04. pii: S2211-1247(21)00407-1. [Epub ahead of print]35(5): 109076
      We lack a mechanistic understanding of aging-mediated changes in mitochondrial bioenergetics and lipid metabolism that affect T cell function. The bioactive sphingolipid ceramide, induced by aging stress, mediates mitophagy and cell death; however, the aging-related roles of ceramide metabolism in regulating T cell function remain unknown. Here, we show that activated T cells isolated from aging mice have elevated C14/C16 ceramide accumulation in mitochondria, generated by ceramide synthase 6, leading to mitophagy/mitochondrial dysfunction. Mechanistically, aging-dependent mitochondrial ceramide inhibits protein kinase A, leading to mitophagy in activated T cells. This aging/ceramide-dependent mitophagy attenuates the antitumor functions of T cells in vitro and in vivo. Also, inhibition of ceramide metabolism or PKA activation by genetic and pharmacologic means prevents mitophagy and restores the central memory phenotype in aging T cells. Thus, these studies help explain the mechanisms behind aging-related dysregulation of T cells' antitumor activity, which can be restored by inhibiting ceramide-dependent mitophagy.
    Keywords:  CerS6; PKA; SS SphK2; T cell; aging; immunotherapy; lipid signaling; melanoma; mitophagy; sphingolipids and ceramide
  6. Int J Mol Sci. 2021 Apr 30. pii: 4793. [Epub ahead of print]22(9):
      Mitochondria are the major source of intercellular bioenergy in the form of ATP. They are necessary for cell survival and play many essential roles such as maintaining calcium homeostasis, body temperature, regulation of metabolism and apoptosis. Mitochondrial dysfunction has been observed in variety of diseases such as cardiovascular disease, aging, type 2 diabetes, cancer and degenerative brain disease. In other words, the interpretation and regulation of mitochondrial signals has the potential to be applied as a treatment for various diseases caused by mitochondrial disorders. In recent years, mitochondrial transplantation has increasingly been a topic of interest as an innovative strategy for the treatment of mitochondrial diseases by augmentation and replacement of mitochondria. In this review, we focus on diseases that are associated with mitochondrial dysfunction and highlight studies related to the rescue of tissue-specific mitochondrial disorders. We firmly believe that mitochondrial transplantation is an optimistic therapeutic approach in finding a potentially valuable treatment for a variety of mitochondrial diseases.
    Keywords:  mitochondria; mitochondrial disease; mitochondrial dysfunction; mitochondrial function; mitochondrial transplantation
  7. Redox Biol. 2021 Apr 23. pii: S2213-2317(21)00124-5. [Epub ahead of print]43 101976
      Mitochondria are central regulators of cellular metabolism, most known for their role in energy production. They can be "enhanced" by physical activity (including exercise), which increases their integrity, efficiency and dynamic adaptation to stressors, in short "mitochondrial fitness". Mitochondrial fitness is closely associated with cardiorespiratory fitness and physical activity. Given the importance of mitochondria in immune functions, it is thus not surprising that cardiorespiratory fitness is also an integral determinant of the antiviral host defense and vulnerability to infection. Here, we first briefly review the role of physical activity in viral infections. We then summarize mitochondrial functions that are relevant for the antiviral immune response with a particular focus on the current Coronavirus Disease (COVID-19) pandemic and on innate immune function. Finally, the modulation of mitochondrial and cardiorespiratory fitness by physical activity, aging and the chronic diseases that represent the most common comorbidities of COVID-19 is discussed. We conclude that a high mitochondrial - and related cardiorespiratory - fitness should be considered as protective factors for viral infections, including COVID-19. This assumption is corroborated by reduced mitochondrial fitness in many established risk factors of COVID-19, like age, various chronic diseases or obesity. We argue for regular analysis of the cardiorespiratory fitness of COVID-19 patients and the promotion of physical activity - with all its associated health benefits - as preventive measures against viral infection.
    Keywords:  COVID; Cardiorespiratory fitness; Exercise; Immune system; Mitochondria; Physical activity; Virus
  8. Br J Surg. 2021 May 08. pii: znab108. [Epub ahead of print]
      BACKGROUND: Ischaemia-reperfusion (IR) injury makes a major contribution to graft damage during kidney transplantation. Oxidative damage to mitochondria is an early event in IR injury. Therefore, the uptake, safety, and efficacy of the mitochondria-targeted antioxidant MitoQ were investigated in models of transplant IR injury.METHODS: MitoQ uptake by warm and cooled pairs of pig and declined human kidneys was measured when preserved in cold static storage or by hypothermic machine perfusion. Pairs of pigs' kidneys were exposed to defined periods of warm and cold ischaemia, flushed and stored at 4°C with or without MitoQ (50 nmol/l to 250 µmol/l), followed by reperfusion with oxygenated autologous blood in an ex vivo normothermic perfusion (EVNP). Pairs of declined human kidneys were flushed and stored with or without MitoQ (5-100 µmol/l) at 4°C for 6 h and underwent EVNP with ABO group-matched blood.
    RESULTS: Stable and concentration-dependent uptake of MitoQ was demonstrated for up to 24 h in pig and human kidneys. Total blood flow and urine output were significantly greater in pig kidneys treated with 50 µmol/l MitoQ compared with controls (P = 0.006 and P = 0.007 respectively). In proof-of-concept experiments, blood flow after 1 h of EVNP was significantly greater in human kidneys treated with 50 µmol/l MitoQ than in controls (P ≤ 0.001). Total urine output was numerically higher in the 50-µmol/l MitoQ group compared with the control, but the difference did not reach statistical significance (P = 0.054).
    CONCLUSION: Mitochondria-targeted antioxidant MitoQ can be administered to ischaemic kidneys simply and effectively during cold storage, and may improve outcomes after transplantation.