bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2022‒07‒24
five papers selected by
Avinash N. Mukkala
University of Toronto

  1. Biochim Biophys Acta Gen Subj. 2022 Jul 13. pii: S0304-4165(22)00121-0. [Epub ahead of print] 130203
      Autophagy-dependent selective degradation of excess or damaged mitochondria, termed mitophagy, is a tightly regulated process necessary for mitochondrial quality and quantity control. Mitochondria are highly dynamic and major sites for vital cellular processes such as ATP and iron‑sulfur cluster biogenesis. Due to their pivotal roles for immunity, apoptosis, and aging, the maintenance of mitochondrial function is of utmost importance for cellular homeostasis. In yeast, mitophagy is mediated by the receptor protein Atg32 that is localized to the outer mitochondrial membrane. Upon mitophagy induction, Atg32 expression is transcriptionally upregulated, which leads to its accumulation on the mitochondrial surface and to recruitment of the autophagic machinery via its direct interaction with Atg11 and Atg8. Importantly, post-translational modifications such as phosphorylation further fine-tune the mitophagic response. This review summarizes the current knowledge about mitophagy in yeast and its connection with mitochondrial dynamics and the ubiquitin-proteasome system.
    Keywords:  Atg11; Atg32; Atg8; Autophagy; Mitochondria; Yeast
  2. Rejuvenation Res. 2022 Jul 19.
      Aging is a natural process in all living organisms defined as destruction of cell function as a result of long-term accumulation of damages. Autophagy is a cellular house safeguard pathway which responsible for degrading damaged cellular organelles. Moreover, it maintains cellular homeostasis, control lifetime, and longevity. Damaged mitochondrial accumulation is a characteristic of aging which associated with neurodegeneration. Mitochondria functions as a principal energy source via supplying ATP through oxidative phosphorylation which serves as fuel for neuronal function. Mitophagy and mitochondrial specific autophagy plays an important role in maintenance of neuronal health via the removal of dysfunctional and aged mitochondria. The mitochondrial QC system involves different strategies for protecting against mitochondrial dysfunction and maintaining healthy mitochondria in cells. Mitochondrial function protection could be a strategy for the promotion of neuroprotection. Mitophagy, could be an effective target for drug discovery. Therefore, further detailed studies for mechanism of mitophagy will advance our mitochondrial phenotype knowledge and understanding to disease pathogenesis. This review mainly focuses on ageing mediated mechanism of autophagy and mitophagy for maintaining the cellular homeostasis and longevity.
  3. Am J Physiol Heart Circ Physiol. 2022 Jul 22.
      Myocardial ischemia has long-lasting negative impacts on cardiomyocyte mitochondrial ATP production. However, the location(s) of damage to the oxidative phosphorylation pathway responsible for altered mitochondrial function is unclear. Mitochondrial reactive oxygen species (ROS) production increases following ischemia, but the specific factors controlling this increase are unknown. To determine how ischemia affects the mitochondrial energy conversion cascade and ROS production, mitochondrial driving forces (redox potential and membrane potential (ΔΨ)) were measured at resting, intermediate, and maximal respiration rates in mitochondria isolated from rat hearts after 60 minutes of control flow (Control) or no-flow ischemia (Ischemia). The effective activities of the dehydrogenase enzymes, the electron transport chain (ETC), and ATP synthesis and transport were computed using the driving forces and flux. Ischemia lowered maximal mitochondrial respiration rates and diminished the responsiveness of respiration to both redox potential and ΔΨ. Ischemia decreased the activities of every component of the oxidative phosphorylation pathway: the dehydrogenase enzymes, the ETC, and ATP synthesis and transport. ROS production was linearly related to driving force down the ETC; however, Ischemia mitochondria demonstrated a greater driving force down the ETC and higher ROS production. Overall, results indicate that ischemia ubiquitously damages the oxidative phosphorylation pathway, reduces mitochondrial sensitivity to driving forces, and augments the propensity for electrons to leak from the ETC. These findings underscore that strategies to improve mitochondrial function following ischemia must target the entire mitochondrial energy conversion cascade.
    Keywords:  cardiac ischemia; metabolic control; mitochondria; reactive oxygen species
  4. Redox Biol. 2022 Jul 16. pii: S2213-2317(22)00182-3. [Epub ahead of print]55 102410
      Some aquaporins (AQPs) can transport H2O2 across membranes, allowing redox signals to proceed in and between cells. Unlike other peroxiporins, human AQP11 is an endoplasmic reticulum (ER)-resident that can conduit H2O2 to the cytosol. Here, we show that silencing Ero1α, an ER flavoenzyme that generates abundant H2O2 during oxidative folding, causes a paradoxical increase in luminal H2O2 levels. The simultaneous AQP11 downregulation prevents this increase, implying that H2O2 reaches the ER from an external source(s). Pharmacological inhibition of the electron transport chain reveals that Ero1α downregulation activates superoxide production by complex III. In the intermembrane space, superoxide dismutase 1 generates H2O2 that enters the ER channeled by AQP11. Meanwhile, the number of ER-mitochondria contact sites increases as well, irrespective of AQP11 expression. Taken together, our findings identify a novel interorganellar redox response that is activated upon Ero1α downregulation and transfers H2O2 from mitochondria to the ER via AQP11.
    Keywords:  Complex III; Hydrogen peroxide; Interorganellar crosstalk/ peroxiporin; Mitochondrial-associated membranes; Redox homeostasis
  5. Stem Cells Transl Med. 2022 Jul 19. pii: szac044. [Epub ahead of print]
      Mesenchymal stromal cells (MSC) have excellent clinical potential and numerous properties that ease its clinical translation. Mitochondria play a crucial role in energy metabolism, essential for cellular activities, such as proliferation, differentiation, and migration. However, mitochondrial dysfunction can occur due to diseases and pathological conditions. Research on mitochondrial transfer from MSCs to recipient cells has gained prominence. Numerous studies have demonstrated that mitochondrial transfer led to increased adenosine triphosphate (ATP) production, recovered mitochondrial bioenergetics, and rescued injured cells from apoptosis. However, the complex mechanisms that lead to mitochondrial transfer from healthy MSCs to damaged cells remain under investigation, and the factors contributing to mitochondrial bioenergetics recovery in recipient cells remain largely ambiguous. Therefore, this review demonstrates an overview of recent findings in preclinical studies reporting MSC mitochondrial transfer, comprised of information on cell sources, recipient cells, dosage, route of administration, mechanism of transfer, pathological conditions, and therapeutic effects. Further to the above, this research discusses the potential challenges of this therapy in its clinical settings and suggestions to overcome its challenges.
    Keywords:  bioenergetics; mesenchymal stromal cell; mitochondrial transfer; preclinical model; tunneling nanotube