bims-mitdyn 2024-12-15 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2024–12–15
six papers selected by
Gavin McStay, Liverpool John Moores University

Phosphorylation of Optineurin by protein kinase D regulates Parkin-dependent mitophagy.
Depleting chemoresponsive mitochondrial fission mediator DRP1 does not mitigate sarcoma resistance.
Mitochondrial dynamics govern whole-body regeneration through stem cell pluripotency and mitonuclear balance.
OPA1 deficiency induces mitophagy through PINK1/Parkin pathway during bovine oocytes maturation.
Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models.
Mitochondrial fission is required for thermogenesis in brown adipose tissue.

iScience. 2024 Dec 20. 27(12): 111384

Phosphorylation of Optineurin by protein kinase D regulates Parkin-dependent mitophagy.

Robert Weil, Emmanuel Laplantine, Messaouda Attailia, Anne Oudin, Shannel Curic, Aya Yokota, Elie Banide, Pierre Génin.

  Degradation of damaged mitochondria, a process called mitophagy, plays a role in mitochondrial quality control and its dysfunction has been linked to neurodegenerative pathologies. The PINK1 kinase and the ubiquitin ligase Parkin-mediated mitophagy represents the most common pathway in which specific receptors, including Optineurin (Optn), target ubiquitin-labeled mitochondria to autophagosomes. Here, we show that Protein Kinases D (PKD) are activated and recruited to damaged mitochondria. Subsequently, PKD phosphorylate Optn to promote a complex with Parkin leading to enhancement of its ubiquitin ligase activity. Paradoxically, inhibiting PKD activity enhances the interaction between Optn and LC3, promotes the recruitment of Parkin to mitochondria, and increases the mitophagic function of Optn. This enhancement of mitophagy is characterized by increased production of mitochondrial ROS and a reduction in mitochondrial mass. The PKD kinases may therefore regulate Optn-dependent mitophagy by amplifying the Parkin-mediated degradation signals to improve the cell response against oxidative stress damage.

Keywords:  Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.111384
Life Sci Alliance. 2025 Feb;pii: e202402870. [Epub ahead of print]8(2):

Depleting chemoresponsive mitochondrial fission mediator DRP1 does not mitigate sarcoma resistance.

Karolina Borankova, Matyas Solny, Maria Krchniakova, Jan Skoda.

Specific patterns of mitochondrial dynamics have been repeatedly reported to promote drug resistance in cancer. However, whether targeting mitochondrial fission- and fusion-related proteins could be leveraged to combat multidrug-resistant pediatric sarcomas is poorly understood. Here, we demonstrated that the expression and activation of the mitochondrial fission mediator DRP1 are affected by chemotherapy exposure in common pediatric sarcomas, namely, rhabdomyosarcoma and osteosarcoma. Unexpectedly, decreasing DRP1 activity through stable DRP1 knockdown neither attenuated sarcoma drug resistance nor affected growth rate or mitochondrial network morphology. The minimal impact on sarcoma cell physiology, along with the up-regulation of fission adaptor proteins (MFF and FIS1) detected in rhabdomyosarcoma cells, suggests an alternative DRP1-independent mitochondrial fission mechanism that may efficiently compensate for the lack of DRP1 activity. By exploring the upstream mitophagy and mitochondrial fission regulator, AMPKα1, we found that markedly reduced AMPKα1 levels are sufficient to maintain AMPK signaling capacity without affecting chemosensitivity. Collectively, our findings challenge the direct involvement of DRP1 in pediatric sarcoma drug resistance and highlight the complexity of yet-to-be-characterized noncanonical regulators of mitochondrial dynamics.

DOI: https://doi.org/10.26508/lsa.202402870
Nat Commun. 2024 Dec 13. 15(1): 10681

Mitochondrial dynamics govern whole-body regeneration through stem cell pluripotency and mitonuclear balance.

Xue Pan, Yun Zhao, Yucong Li, Jiajia Chen, Wenya Zhang, Ling Yang, Yuanyi Zhou Xiong, Yuqing Ying, Hao Xu, Yuhong Zhang, Chong Gao, Yuhan Sun, Nan Li, Liangyi Chen, Zhixing Chen, Kai Lei.

Tissue regeneration is a complex process involving large changes in cell proliferation, fate determination, and differentiation. Mitochondrial dynamics and metabolism play a crucial role in development and wound repair, but their function in large-scale regeneration remains poorly understood. Planarians offer an excellent model to investigate this process due to their remarkable regenerative abilities. In this study, we examine mitochondrial dynamics during planarian regeneration. We find that knockdown of the mitochondrial fusion gene, opa1, impairs both tissue regeneration and stem cell pluripotency. Interestingly, the regeneration defects caused by opa1 knockdown are rescued by simultaneous knockdown of the mitochondrial fission gene, drp1, which partially restores mitochondrial dynamics. Furthermore, we discover that Mitolow stem cells exhibit an enrichment of pluripotency due to their fate choices at earlier stages. Transcriptomic analysis reveals the delicate mitonuclear balance in metabolism and mitochondrial proteins in regeneration, controlled by mitochondrial dynamics. These findings highlight the importance of maintaining mitochondrial dynamics in large-scale tissue regeneration and suggest the potential for manipulating these dynamics to enhance stem cell functionality and regenerative processes.

DOI: https://doi.org/10.1038/s41467-024-54720-1
Theriogenology. 2024 Dec 04. pii: S0093-691X(24)00497-7. [Epub ahead of print]234 51-63

OPA1 deficiency induces mitophagy through PINK1/Parkin pathway during bovine oocytes maturation.

Tiancang Han, Yuhan Zhao, Anhui Jiao, Zhaoyang Sun, Hongbo Zhang, Dazhuo Zhao, Haijun Wang, Qingshan Gao.

  In vitro embryo production (IVP) technology has been increasingly applied to beef cattle breeding. In vitro maturation (IVM) technology is the basis of IVP. However, the quality of in vitro-generated mature oocytes is still poor. Mitochondria are the energy factories of oocytes, so they are crucial for oocyte quality. OPA1 is a protein located on the mitochondrial inner membrane, and its main function is to mediate mitochondrial inner membrane fusion. This work demonstrated that OPA1 is expressed at different stages of meiosis in bovine oocytes. The inhibition of OPA1 activity resulted in a reduced rate of first polar body excretion from bovine oocytes and disruption of the spindle structure. OPA1 deficiency impacted mitochondria by leading to mitochondrial dysfunction, promoting mitochondrial fission, and inducing mitophagy through the PINK1/Parkin pathway. Taken together, our findings suggest that OPA1 is essential for bovine oocyte maturation and that OPA1 deficiency leads to mitochondrial dysfunction and promotes mitochondrial fission as well as mitophagy.

Keywords:  Bovine oocyte; Mitophagy; OPA1; PINK1; Parkin

DOI:  https://doi.org/10.1016/j.theriogenology.2024.12.004
Brain Commun. 2024 ;6(6): fcae404

Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models.

Jacques Bureau, Florence Manero, Olivier Baris, Alexia Bodin, Christophe Verny, Arnaud Chevrollier, Guy Lenaers, Philippe Codron.

  Hereditary optic neuropathies, including dominant optic atrophy and Leber's hereditary optic neuropathy, are genetic disorders characterized by retinal ganglion cell degeneration leading to vision loss, mainly associated with mitochondrial dysfunction. In this study, we analysed mitochondrial distribution and ultrastructure in the retina and longitudinal optic nerve sections of pre-symptomatic hereditary optic neuropathies mouse models with Opa1 and Nd6 deficiency to identify early mitochondrial changes. Our results show significant mitochondrial fragmentation and increased mitophagy in Opa1+/- mice, indicating early mitochondrial changes prior to neuronal loss. Conversely, Nd6P25L mice exhibited mitochondrial hypertrophy, suggesting an adaptive response to compensate for altered energy metabolism. These pre-symptomatic mitochondrial changes were mainly observed in the unmyelinated portion of the retinal ganglion cell axons, where the transmission of the visual information requires high energy expenditure, constituting the specific point of vulnerability in hereditary optic neuropathies. These findings highlight early focal mitochondrial changes prior to neuronal loss in hereditary optic neuropathies and provide insight into pre-symptomatic therapeutic approaches.

Keywords:  Leber hereditary optic neuropathy; Opa1; dominant optic atrophy; hereditary optic neuropathy; mitochondria

DOI:  https://doi.org/10.1093/braincomms/fcae404
PLoS One. 2024 ;19(12): e0312352

Mitochondrial fission is required for thermogenesis in brown adipose tissue.

Yuta Ibayashi, Nao Hasuzawa, Seiji Nomura, Masaharu Kabashima, Ayako Nagayama, Shimpei Iwata, Miyuki Kitamura, Kenji Ashida, Yoshinori Moriyama, Ken Yamamoto, Masatoshi Nomura, Lixiang Wang.

Brown adipose tissue (BAT) thermogenesis is pivotal for maintaining body temperature and energy balance. Mitochondrial morphology is dynamically controlled by a balance between fusion and fission, which is crucial for cell differentiation, response to metabolic insults, and heat production. Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission. This study investigates the role of Drp1 in BAT development and thermogenesis by generating Drp1-deficient mice. These mice were created by crossing Drp1 floxed mice with fatty acid-binding protein 4-Cre (aP2-Cre) transgenic mice, resulting in aP2-Cre+/-Drp1flox/flox (aP2-Drp1f/f) mice. The aP2-Drp1f/f mice exhibited severe BAT and brain hypoplasia, with the majority dying within 48 hours postnatally, highlighting Drp1's crucial role in neonatal survival. Impaired thermogenic responses were observed in aP2-Drp1f/f mice, characterized by significantly decreased expression of thermogenic and lipogenic genes in BAT. Ultrastructural analysis revealed disrupted mitochondrial morphology and reduced lipid droplet content in BAT. The few surviving adult aP2-Drp1f/f mice also showed impaired BAT and brain development, along with BAT thermogenesis dysfunction during cold exposure. Our findings underscore the essential role of Drp1-mediated mitochondrial fission in BAT thermogenesis and neonatal survival, providing insights into potential therapeutic approaches for metabolic disorders.

DOI: https://doi.org/10.1371/journal.pone.0312352