bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024‒04‒14
seven papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
  2. GTPBP8 modulates mitochondrial fission through a Drp1-dependent process.
  3. Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons.
  4. Bacterial muropeptides promote OXPHOS and suppress mitochondrial stress in mammals.
  5. Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria.
  6. Mitochondrial Ca2+ signaling is a hallmark of specific adipose tissue-cancer crosstalk.
  7. MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX.
  1. Nat Cell Biol. 2024 Apr 09.
    Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
    Ao Liu, Frieda Kage, Asan F Abdulkareem, Mac Pholo Aguirre-Huamani, Gracie Sapp, Halil Aydin, Henry N Higgs.
      Mitochondrial fission occurs in many cellular processes, but the regulation of fission is poorly understood. We show that long-chain acyl-coenzyme A (LCACA) activates two related mitochondrial fission proteins, MiD49 and MiD51, by inducing their oligomerization, which activates their ability to stimulate the DRP1 GTPase. The 1:1 stoichiometry of LCACA:MiD in the oligomer suggests interaction in the previously identified nucleotide-binding pocket, and a point mutation in this pocket reduces LCACA binding and LCACA-induced oligomerization for MiD51. In cells, this LCACA binding mutant does not assemble into puncta on mitochondria or rescue MiD49/51 knockdown effects on mitochondrial length and DRP1 recruitment. Furthermore, cellular treatment with BSA-bound oleic acid, which causes increased LCACA, promotes mitochondrial fission in an MiD49/51-dependent manner. These results suggest that LCACA is an endogenous ligand for MiDs, inducing mitochondrial fission and providing a potential mechanism for fatty-acid-induced mitochondrial division. Finally, MiD49 or MiD51 oligomers synergize with Mff, but not with actin filaments, in DRP1 activation, suggesting distinct pathways for DRP1 activation.
    DOI:  https://doi.org/10.1038/s41556-024-01400-3
  2. J Cell Sci. 2024 Apr 08. pii: jcs.261612. [Epub ahead of print]
    GTPBP8 modulates mitochondrial fission through a Drp1-dependent process.
    Xiumei He, Liang Wang, Hoi Ying Tsang, Xiaonan Liu, Xiaofeng Yang, Ziqi Guo, Cheng Yang, Qiong Wu, Zuping Zhou, Xiaobo Cen, Hongxia Zhao.
      Mitochondrial fission is a tightly regulated process involving multiple proteins and cell signaling. Despite extensive studies on mitochondrial fission factors, our understanding of the regulatory mechanisms remains limited. This study shows the critical role of a mitochondrial GTPase, GTPBP8, in orchestrating mitochondrial fission. Depletion of GTPBP8 resulted in drastic elongation and interconnectedness of mitochondria. Conversely, overexpression of GTPBP8 shifted mitochondrial morphology from tubular to fragmented. Notably, the induced mitochondrial fragmentation from GTPBP8 overexpression was inhibited in cells either depleted of the mitochondrial fission protein Drp1 or carrying mutated forms of Drp1. Importantly, downregulation of GTPBP8 caused an increase in oxidative stress, modulating cell signaling involved in the heightened phosphorylation of Drp1 at Ser637. This phosphorylation hindered the recruitment of Drp1 to mitochondria, leading to mitochondrial fission defects. On the other hand, GTPBP8 overexpression triggered enhanced recruitment and assembly of Drp1 to mitochondria. In summary, our study illuminates the cellular function of GTPBP8 as a pivotal modulator of the mitochondrial division apparatus, inherently reliant on its influence on Drp1.
    Keywords:  Drp1; Fission; GTPBP8; Mitochondria; Phosphorylation
    DOI:  https://doi.org/10.1242/jcs.261612
  3. Neuron. 2024 Mar 26. pii: S0896-6273(24)00167-3. [Epub ahead of print]
    Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons.
    Sandra M V Kochan, Meret Cepero Malo, Milica Jevtic, Hannah M Jahn-Kelleter, Gulzar A Wani, Kristiano Ndoci, Laura Pérez-Revuelta, Felix Gaedke, Iris Schäffner, Dieter Chichung Lie, Astrid Schauss, Matteo Bergami.
      Integration of new neurons into adult hippocampal circuits is a process coordinated by local and long-range synaptic inputs. To achieve stable integration and uniquely contribute to hippocampal function, immature neurons are endowed with a critical period of heightened synaptic plasticity, yet it remains unclear which mechanisms sustain this form of plasticity during neuronal maturation. We found that as new neurons enter their critical period, a transient surge in fusion dynamics stabilizes elongated mitochondrial morphologies in dendrites to fuel synaptic plasticity. Conditional ablation of fusion dynamics to prevent mitochondrial elongation selectively impaired spine plasticity and synaptic potentiation, disrupting neuronal competition for stable circuit integration, ultimately leading to decreased survival. Despite profuse mitochondrial fragmentation, manipulation of competition dynamics was sufficient to restore neuronal survival but left neurons poorly responsive to experience at the circuit level. Thus, by enabling synaptic plasticity during the critical period, mitochondrial fusion facilitates circuit remodeling by adult-born neurons.
    Keywords:  LTP; Mfn2; adult neurogenesis; competition; experience; hippocampus; mitochondria; mitochondrial fusion; neural stem cell; synaptic plasticity
    DOI:  https://doi.org/10.1016/j.neuron.2024.03.013
  4. Cell Rep. 2024 Apr 06. pii: S2211-1247(24)00395-4. [Epub ahead of print]43(4): 114067
    Bacterial muropeptides promote OXPHOS and suppress mitochondrial stress in mammals.
    Dong Tian, Mingxue Cui, Min Han.
      Mitochondrial dysfunction critically contributes to many major human diseases. The impact of specific gut microbial metabolites on mitochondrial functions of animals and the underlying mechanisms remain to be uncovered. Here, we report a profound role of bacterial peptidoglycan muropeptides in promoting mitochondrial functions in multiple mammalian models. Muropeptide addition to human intestinal epithelial cells (IECs) leads to increased oxidative respiration and ATP production and decreased oxidative stress. Strikingly, muropeptide treatment recovers mitochondrial structure and functions and inhibits several pathological phenotypes of fibroblast cells derived from patients with mitochondrial disease. In mice, muropeptides accumulate in mitochondria of IECs and promote small intestinal homeostasis and nutrient absorption by modulating energy metabolism. Muropeptides directly bind to ATP synthase, stabilize the complex, and promote its enzymatic activity in vitro, supporting the hypothesis that muropeptides promote mitochondria homeostasis at least in part by acting as ATP synthase agonists. This study reveals a potential treatment for human mitochondrial diseases.
    Keywords:  ATP synthase; CP: Cell biology; CP: Metabolism; Leigh syndrome; PGN; ROS; antibiotic-induced microbiome depletion; electron transfer chain; energy metabolism; intestinal epithelial cells; intestinal homeostasis; mitochondrial diseases; oxidative phosphorylation; oxidative stress; peptidoglycan
    DOI:  https://doi.org/10.1016/j.celrep.2024.114067
  5. J Biol Chem. 2024 Apr 06. pii: S0021-9258(24)01770-8. [Epub ahead of print] 107269
    Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria.
    Laura H Steenberge, Sean Rogers, Andrew Y Sung, Jing Fan, David J Pagliarini.
      Coenzyme Q10 (CoQ10) is an important cofactor and antioxidant for numerous cellular processes, and its deficiency has been linked to human disorders including mitochondrial disease, heart failure, Parkinson's disease, and hypertension. Unfortunately, treatment with exogenous CoQ10 is often ineffective, likely due to the extreme hydrophobicity and high molecular weight of CoQ10. Here, we show that less hydrophobic CoQ species with shorter isoprenoid tails can serve as viable substitutes for CoQ10 in human cells. We demonstrate that CoQ4 can perform multiple functions of CoQ10 in CoQ-deficient cells at markedly lower treatment concentrations, motivating further investigation of CoQ4 as a supplement for CoQ10 deficiencies. In addition, we describe the synthesis and evaluation of an initial set of compounds designed to target CoQ4 selectively to mitochondria using triphenylphosphonium (TPP). Our results indicate that select versions of these compounds can successfully be delivered to mitochondria in a cell model and be cleaved to produce CoQ4, laying the groundwork for further development.
    Keywords:  Antioxidant; Bioenergetics; Coenzyme Q10 (CoQ10); Ferroptosis; Membrane lipid; Mitochondrial respiratory chain complex; Mitochondrial therapeutics; Pyrimidine biosynthesis; Ubiquinone
    DOI:  https://doi.org/10.1016/j.jbc.2024.107269
  6. Sci Rep. 2024 Apr 11. 14(1): 8469
    Mitochondrial Ca2+ signaling is a hallmark of specific adipose tissue-cancer crosstalk.
    Agnese De Mario, Elisabetta Trevellin, Ilaria Piazza, Vincenzo Vindigni, Mirto Foletto, Rosario Rizzuto, Roberto Vettor, Cristina Mammucari.
      Obesity is associated with increased risk and worse prognosis of many tumours including those of the breast and of the esophagus. Adipokines released from the peritumoural adipose tissue promote the metastatic potential of cancer cells, suggesting the existence of a crosstalk between the adipose tissue and the surrounding tumour. Mitochondrial Ca2+ signaling contributes to the progression of carcinoma of different origins. However, whether adipocyte-derived factors modulate mitochondrial Ca2+ signaling in tumours is unknown. Here, we show that conditioned media derived from adipose tissue cultures (ADCM) enriched in precursor cells impinge on mitochondrial Ca2+ homeostasis of target cells. Moreover, in modulating mitochondrial Ca2+ responses, a univocal crosstalk exists between visceral adipose tissue-derived preadipocytes and esophageal cancer cells, and between subcutaneous adipose tissue-derived preadipocytes and triple-negative breast cancer cells. An unbiased metabolomic analysis of ADCM identified creatine and creatinine for their ability to modulate mitochondrial Ca2+ uptake, migration and proliferation of esophageal and breast tumour cells, respectively.
    DOI:  https://doi.org/10.1038/s41598-024-55650-0
  7. Autophagy. 2024 Apr 10.
    MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX.
    Mohamed A Eldeeb, Armaan Fallahi, Andrea Soumbasis, Andrew N Bayne, Jean-François Trempe, Edward A Fon.
      Mutations in the PINK1 kinase cause Parkinson disease (PD) through physiological processes that are not yet fully elucidated. PINK1 kinase accumulates selectively on damaged mitochondria, where it recruits the E3 ubiquitin ligase PRKN/Parkin to mediate mitophagy. Upon mitochondrial import failure, PINK1 accumulates in association with the translocase of outer mitochondrial membrane (TOMM). However, the molecular basis of this PINK1 accumulation on the TOMM complex remain elusive. We recently demonstrated that TIMM23 (translocase of the inner mitochondrial membrane 23) is a component of the PINK1-supercomplex formed in response to mitochondrial stress. We also uncovered that PINK1 is required for the formation of this supercomplex and highlighted the biochemical regulation and significance of this supercomplex; expanding our understanding of mitochondrial quality control and PD pathogenesis.
    Keywords:  Mitochondrial import; PINK1; Parkinson’s disease; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2340399
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