bims-mecosi 2024-07-28 papers

Issue of 2024‒07‒28
four papers selected by
Verena Kohler, Umeå University

J Neurosci. 2024 Jul 25. pii: e0879242024. [Epub ahead of print]

ALS-linked VapB P56S mutation alters neuronal mitochondrial turnover at the synapse.

Hiu-Tung C Wong, Angelica E Lang, Chris Stein, Catherine M Drerup.

Mitochondrial population maintenance in neurons is essential for neuron function and survival. Contact sites between mitochondria and the endoplasmic reticulum (ER) are poised to regulate mitochondrial homeostasis in neurons. These contact sites can function to facilitate transfer of calcium and lipids between the organelles and have been shown to regulate aspects of mitochondrial fission and fusion dynamics. VapB is an ER membrane protein present at a subset of ER-mitochondria contact sites. Mutations in VapB cause neurodegenerative disease. Specifically, a proline-to-serine mutation at amino acid 56 (P56S), correlates with susceptibility to amyotrophic lateral sclerosis (ALS) type 8. Given the relationship between failed mitochondrial health and neurodegenerative disease, we investigated the function of VapB in mitochondrial population maintenance. We demonstrate that transgenic expression of VapBP56S in zebrafish larvae (sex undetermined) increased mitochondrial biogenesis, causing increased mitochondrial population size in the axon terminal. Expression of wild type VapB did not alter biogenesis but, instead, increased mitophagy in the axon terminal. Using genetic manipulations to independently increase mitochondrial biogenesis in zebrafish neurons, we show that biogenesis is normally balanced by mitophagy to maintain a constant mitochondrial population size. VapBP56S transgenics fail to increase mitophagy to compensate for the increase in mitochondrial biogenesis, suggesting an impaired mitophagic response. Finally, using a synthetic ER-mitochondria tether, we show that VapB's function in mitochondrial turnover is likely independent of ER-mitochondrial tethering by contact sites. Our findings demonstrate that VapB can control mitochondrial turnover in the axon terminal, and this function is altered by the P56S ALS-linked mutation.Significance statement Mitochondrial population dysfunction is tightly tied to neurodegenerative diseases, including ALS. Maintenance of the mitochondrial population in neurons requires the birth of new mitochondria and the degradation of damaged organelles. ER-mitochondrial contact site proteins are in a position to regulate both processes in neurons. Our work demonstrates that an ALS-associated mutation in the contact site protein VapB disrupts both processes, identifying VapB as a mediator of regulated mitochondrial turnover to maintain a steady-state mitochondrial population.

DOI: https://doi.org/10.1523/JNEUROSCI.0879-24.2024

J Exp Bot. 2024 Jul 22. pii: erae313. [Epub ahead of print]

Proximity driven plastid-nucleus relationships are facilitated by tandem plastid-ER dynamics.

Thomas Kadanthottu Kunjumon, Puja Puspa Ghosh, Laura M J Currie, Jaideep Mathur.

Peri-nuclear clustering (PNC) of chloroplasts has largely been described in senescent and pathogen- or ROS- stressed cells. Stromules, tubular plastid extensions are also observed under similar conditions. Coincident observations of PNC and stromules associate the two phenomena in facilitating retrograde signaling between chloroplasts and the nucleus. However, PNC incidence in non-stressed cells under normal growth and developmental conditions, when stromules are usually not observed, remains unclear. Using transgenic Arabidopsis expressing different organelle-targeted fluorescent proteins we show that PNC is a dynamic subcellular phenomenon that continues in the absence of light and is not dependent on stromule formation. PNC is facilitated by tandem plastid-ER dynamics created through membrane contact sites between the two organelles. While PNC increases upon ER-membrane expansion, some plastids may remain in the peri-nuclear region due to their localization in ER-lined nuclear indentions. Moreover, some PNC plastids may sporadically extend stromules into ER-lined nuclear grooves. Our findings strongly suggest that PNC is not an exclusive response to stress caused by pathogens, high light or exogenous-H2O2 treatment and does not require stromule formation. However, morphological and behavioural alterations in ER and concomitant changes in tandem, plastid-ER dynamics play a major role in facilitating the phenomenon.

Keywords: Chloroplast-interactions; ER; Fluorescent proteins; Membrane contact sites (MCS); Peri-nuclear ER; Plastid-nucleus relationship

DOI: https://doi.org/10.1093/jxb/erae313

Int J Mol Sci. 2024 Jul 16. pii: 7776. [Epub ahead of print]25(14):

Analysis of Brain, Blood, and Testis Phenotypes Lacking the Vps13a Gene in C57BL/6N Mice.

Jitrapa Pinyomahakul, Masataka Ise, Meiko Kawamura, Takashi Yamada, Kentaro Okuyama, Shinsuke Shibata, Jun Takizawa, Manabu Abe, Kenji Sakimura, Hirohide Takebayashi.

The Vps13a gene encodes a lipid transfer protein called VPS13A, or chorein, associated with mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondria-endosomes, and lipid droplets. This protein plays a crucial role in inter-organelle communication and lipid transport. Mutations in the VPS13A gene are implicated in the pathogenesis of chorea-acanthocytosis (ChAc), a rare autosomal recessive neurodegenerative disorder characterized by chorea, orofacial dyskinesias, hyperkinetic movements, seizures, cognitive impairment, and acanthocytosis. Previous mouse models of ChAc have shown variable disease phenotypes depending on the genetic background. In this study, we report the generation of a Vps13a flox allele in a pure C57BL/6N mouse background and the subsequent creation of Vps13a knockout (KO) mice via Cre-recombination. Our Vps13a KO mice exhibited increased reticulocytes but not acanthocytes in peripheral blood smears. Additionally, there were no significant differences in the GFAP- and Iba1-positive cells in the striatum, the basal ganglia of the central nervous system. Interestingly, we observed abnormal spermatogenesis leading to male infertility. These findings indicate that Vps13a KO mice are valuable models for studying male infertility and some hematological aspects of ChAc.

Keywords: VPS13A (vascular protein sorting 13A)/chorein; chorea-acanthocytosis (ChAc); conditional allele; knockout (KO) mice; lipid droplet; mitochondria-associated endoplasmic reticulum membranes (MAMs)

DOI: https://doi.org/10.3390/ijms25147776

Nat Commun. 2024 Jul 21. 15(1): 6143

ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.

Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP3R-mediated Ca2+ transfer from ER to mitochondria and decreased mitochondrial Ca2+ uptake. In turn, reduced mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal health.

DOI: https://doi.org/10.1038/s41467-024-50502-x