bims-mecmid Biomed News
on Membrane communication in mitochondrial dynamics
Issue of 2021‒12‒26
six papers selected by
Mauricio Cardenas Rodriguez
University of Padova

  1. Cell Rep. 2021 Dec 21. pii: S2211-1247(21)01637-5. [Epub ahead of print]37(12): 110141
      Neurons are highly polarized cells that display characteristic differences in the organization of their organelles in axons and dendrites. The kinases SadA and SadB (SadA/B) promote the formation of distinct axonal and dendritic extensions during the development of cortical and hippocampal neurons. Here, we show that SadA/B are required for the specific dynamics of axonal mitochondria. Ankyrin B (AnkB) stimulates the activity of SadA/B that function as regulators of mitochondrial dynamics through the phosphorylation of tau. Suppression of SadA/B or AnkB in cortical neurons induces the elongation of mitochondria by disrupting the balance of fission and fusion. SadA/B-deficient neurons show an accumulation of hyper-fused mitochondria and activation of the integrated stress response (ISR). The normal dynamics of axonal mitochondria could be restored by mild actin destabilization. Thus, the elongation after loss of SadA/B results from an excessive stabilization of actin filaments and reduction of Drp1 recruitment to mitochondria.
    Keywords:  Ankyrin; Brsk1; Brsk2; Drp1; F-actin; Mapt; hyperfusion; mitochondrial dynamics; mitochondrial fission; neuronal polarity
  2. Front Cardiovasc Med. 2021 ;8 770574
      Vascular diseases, particularly atherosclerosis, are associated with high morbidity and mortality. Endothelial cell (EC) or vascular smooth muscle cell (VSMC) dysfunction leads to blood vessel abnormalities, which cause a series of vascular diseases. The mitochondria are the core sites of cell energy metabolism and function in blood vessel development and vascular disease pathogenesis. Mitochondrial dynamics, including fusion and fission, affect a variety of physiological or pathological processes. Multiple studies have confirmed the influence of mitochondrial dynamics on vascular diseases. This review discusses the regulatory mechanisms of mitochondrial dynamics, the key proteins that mediate mitochondrial fusion and fission, and their potential effects on ECs and VSMCs. We demonstrated the possibility of mitochondrial dynamics as a potential target for the treatment of vascular diseases.
    Keywords:  cardiovascular disease (CVDs); fission; fusion; mitochondrial dynamics; vascular diseases
  3. Biomolecules. 2021 Nov 27. pii: 1779. [Epub ahead of print]11(12):
      Emerging evidence shows that mitochondria fusion/fission imbalance is related to the occurrence of hyperglycemia-induced vascular injury. To study the temporal dynamics of mitochondrial fusion and fission, we observed the alteration of mitochondrial fusion/fission proteins in a set of different high-glucose exposure durations, especially in the early stage of hyperglycemia. The in vitro results show that persistent cellular apoptosis and endothelial dysfunction can be induced rapidly within 12 hours' high-glucose pre-incubation. Our results show that mitochondria maintain normal morphology and function within 4 hours' high-glucose pre-incubation; with the extended high-glucose exposure, there is a transition to progressive fragmentation; once severe mitochondria fusion/fission imbalance occurs, persistent cellular apoptosis will develop. In vitro and in vivo results consistently suggest that mitochondrial fusion/fission homeostasis alterations trigger high-glucose-induced vascular injury. As the guardian of mitochondria, AMPK is suppressed in response to hyperglycemia, resulting in imbalanced mitochondrial fusion/fission, which can be reversed by AMPK stimulation. Our results suggest that mitochondrial fusion/fission's staged homeostasis may be a predictive factor of diabetic cardiovascular complications.
    Keywords:  AMPK; endothelial dysfunction; fusion/fission; metabolic memory; mitochondria dynamics
  4. Int J Biochem Cell Biol. 2021 Dec 16. pii: S1357-2725(21)00218-1. [Epub ahead of print] 106137
      Friedreich ataxia is an autosomal recessive congenital neurodegenerative disease caused by a deficiency in the frataxin protein and is often diagnosed in young adulthood. An expansion of guanine-adenine-adenine repeats in the first intron of the FXN gene leads to decreased frataxin expression. Frataxin plays an essential role in mitochondrial metabolism. Most Friedreich ataxia patients are diagnosed with left ventricular hypertrophic cardiomyopathy, and 60% of patients die with hypertrophic cardiomyopathy. However, the mitochondrial anatomy in Friedreich ataxia hypertrophic cardiomyopathy is still poorly understood. We investigated mitochondrial fission, fusion, and function using biochemical, microscopy, and computational stochastic analysis in human induced pluripotent stem cell derived cardiomyocytes from a patient with Friedreich ataxia hypertrophic cardiomyopathy and a healthy individual. We found a significantly higher mitochondrial footprint, decreased mitochondrial fission protein dynamin-related protein, and mitochondrial fission rate over fusion with more giant mitochondrial clusters in human induced pluripotent stem cell derived cardiomyocytes from a patient with Friedreich ataxia hypertrophic cardiomyopathy, compared to an unaffected individual. We also found significantly depolarized mitochondrial membrane potential and higher reactive oxygen species levels in Friedreich ataxia human induced pluripotent stem cell cardiomyocytes. Our results show that frataxin's depletion may dampen the mitochondrial fission machinery by reducing dynamin-related protein1. The loss of mitochondrial fission might lead to elevated reactive oxygen species and depolarized mitochondrial membrane potential, which may cause oxidative damage in Friedreich ataxia hypertrophic cardiomyopathy. Further investigations are needed to identify the mechanism of downregulating dynamin-related protein1 due to the frataxin deficiency in Friedreich ataxia hypertrophic cardiomyopathy.
    Keywords:  DRP1; Friedreich ataxia; hypertrophic cardiomyopathy; mitochondrial fusion and fission
  5. Toxicol Appl Pharmacol. 2021 Dec 18. pii: S0041-008X(21)00437-3. [Epub ahead of print]435 115833
      Clinical utilization of doxorubicin (DOX), which is a commonly used chemotherapeutic, is restricted due to toxic effects on various tissues. Using hesperetin (HST), an antioxidant used in Chinese traditional medicine protects testis against DOX-induced toxicity although the molecular mechanisms are not well-known. The study was aimed to examine the possible role of the mechanistic target of rapamycin kinase (mTOR) and dynamin 1-like dynamin-related protein 1 (DRP1) in the therapeutic effects of HST on the DOX-induced testicular toxicity. Rats were divided into Control, DOX, DOX + HST, and HST groups (n = 7). Single-dose DOX (15 mg/kg) was administered intraperitoneally and HST (50 mg/kg) was administered by oral gavage every other day for 28 days. Total antioxidant status (TAS), histopathological evaluations, immunohistochemistry, and gene expression level detection analyses were performed. Histopathologically, DOX-induced testicular damage was ameliorated by HST treatment. DOX reduced testicular TAS levels and increased oxidative stress markers, 8-Hydroxy-deoxyguanosine (8-OHdG), and 4-Hydroxynonenal (4-HNE). Also, upregulated mTOR and DRP1 expressions with DOX exposure were decreased after HST treatment in the testis (p < 0.05). On the other hand, DOX-administration downregulated miR-150-5p and miR-181b-2-3p miRNAs, targeting mTOR and mRNA levels of beclin 1 (BECN1) and autophagy-related 5 (ATG5), autophagic markers. Furthermore, these levels were nearly similar to control testis samples in the DOX + HST group (p < 0.05). The study demonstrated that HST may have a therapeutic effect on DOX-induced testicular toxicity by removing reactive oxygen species (ROS) and by modulating the mTOR and DRP1 expressions, which have a critical role in regulating the balance of generation/elimination of ROS.
    Keywords:  DRP1; Doxorubicin; Hesperetin; Testis; mTOR
  6. Toxicology. 2021 Dec 21. pii: S0300-483X(21)00404-2. [Epub ahead of print] 153082
      Cadmium (Cd) is an important environmental pollutant that causes varying degrees of damage to multiple systems of the body. However, the specific mechanism of Cd-induced liver mitophagy remains unclear. In the present study, 5-week-old BALB/c mice and a mouse liver parenchyma cell line (AML12) were studied using a combination of in vivo and in vitro studies. We found that Cd damaged liver cells, destroy the structure and function of mitochondria, and increased the production of superoxide anions. This study further examined the effect of Cd on mitochondrial dynamics and mitophagy and showed that Cd increased mitochondrial division and induced mitophagy. The PINK1-Parkin pathway is a classical mitophagy pathway. Cd-induced mitophagy was inhibited after significantly knocking down Pink1. Mdivi-1 can effectively inhibit mitochondrial division. In this study, Mdivi-1 inhibited the expression of DRP1 and significantly inhibited the occurrence of mitophagy induced by Cd. We further examined the effect of Cd on mitophagy flux. Cd did not increase lysosomal colocalization with mitochondria. In summary, Cd increase the level of oxidative stress, destroy the structure and function of mitochondria, destroy the homeostasis of mitochondrial division and fusion, induce mitophagy through the PINK1-Parkin pathway. Mitophagy plays a protective role in early cadmium-induced liver damage.
    Keywords:  Cadmium; DRP1; Liver; Mitochondria; Mitophagy; PINK1; Parkin