Biology subjects

Ahier, A.

Publications and source records attributed to Ahier, A..

5 recordsLinked to original sources

bioRxiv2026

Germline mitophagy selectively eliminates deleterious mitochondrial DNA across generations

Faithful transmission of genetic information through the immortal germline is essential for organismal health and species survival, yet how mutant mitochondrial genomes (mtDNAs) are selectively eliminated across generations remains unclear. Here, we show that germline mitophagy functions as a mutation-responsive surveillance system that selectively eliminates mutant mtDNAs and shapes inheritance across generations. In C. elegans, mitochondria enriched for mutant mtDNAs are selectively removed in the maternal germline prior to oocyte fertilization via PINK1/Parkin-dependent and BNIP3-mediated mitophagy pathways activated by mtDNA defects. Germline mitophagy declines with age, resulting in offspring that inherit increased burdens of mutant mtDNAs. Conversely, enhancing mitophagy within germ cells restricts the transmission of deleterious genomes in a compounding manner, ultimately driving their complete elimination from the matrilineal lineage. Together, our findings demonstrate that germline mitophagy is a critical determinant of intergenerational mitochondrial genome inheritance, establishing its role in restricting the transmission of defective genetic information.

Cell Biology↗

bioRxiv2024

Essential and dual effects of Notch activity on a natural transdifferentiation event

Cell identity can be reprogrammed, naturally or experimentally, albeit with low frequency. Why given cells, but not their neighbours, undergo a cell identity conversion remains unclear. We find that Notch signalling plays a key role to promote natural transdifferentiation in C. elegans. Endogenous Notch signal endows a cell with the competence to transdifferentiate by promoting plasticity factors expression (hlh-16/Olig and sem-4/Sall). Strikingly, exogenous Notch can trigger ectopic transdifferentiation in vivo. However, Notch signalling can both promote and block transdifferentiation depending on its activation timing. Notch only promotes transdifferentiation during an early precise window of opportunity and signal duration must be tightly controlled in time. Our findings emphasise the importance of temporality and dynamics of the underlying molecular events preceding the initiation of natural cell reprogramming. Finally, our results support a model where both an extrinsic signal and the intrinsic cellular context combine to empower a cell with the competence to transdifferentiate.

developmental biology↗

bioRxiv2023

Misregulation of mitochondrial 6mA promotes the propagation of mutant mtDNA and causes aging in C. elegans

In virtually all eukaryotes, the mitochondrial genome (mitochondrial DNA, mtDNA) encodes proteins necessary for oxidative phosphorylation (OXPHOS) and the RNA machinery required for their synthesis inside the mitochondria. Appropriate regulation of mtDNA copy number and expression is essential for ensuring the correct stoichiometric formation of OXPHOS complexes assembled from both nuclear- and mtDNA-encoded subunits. The mechanisms of mtDNA regulation are not completely understood but are essential to organismal viability and lifespan. Here, using multiple approaches, we identify the presence of N6-methylation (6mA) on the mtDNA of diverse animal and plant species. Importantly, we also demonstrate that this modification is regulated in C. elegans by the DNA methyltransferase DAMT-1, and DNA demethylase ALKB-1, which localize to mitochondria. Misregulation of mtDNA 6mA through targeted overexpression of these enzymatic activities inappropriately alters mtDNA copy number and expression, impairing OXPHOS function and producing increased oxidative stress, as well as a shortened lifespan. Compounding defects in mtDNA regulation, reductions in mtDNA 6mA methylation promote the propagation of a deleterious mitochondrial genome across generations. Together, these results reveal that mtDNA 6mA is highly conserved among eukaryotes and regulates lifespan by influencing mtDNA copy number, expression, and heritable mutation levels in vivo.

molecular biology↗

bioRxiv2021

A natural transdifferentiation event involving mitosis is empowered by integrating signaling inputs with conserved plasticity factors

Transdifferentiation, or direct cell reprogramming, is the direct conversion of one fully differentiated cell type into another. Whether core mechanisms are shared between different transdifferentiation events, which can occur naturally in presence or in absence of cell division, is unclear. Our lab has previously characterized the Y-to-PDA natural transdifferentiation in Caenorhabditis elegans, which occurs without cell division and requires orthologs of vertebrates reprogramming factors. In this study, focusing on another transdifferentiation process, the K rectal cell-to-DVB GABAergic neuron, we report that the Y-to-PDA reprogramming factor SEM-4/SALL, SOX-2, CEH-6/POU are required for K-to-DVB transdifferentiation to allow the erasure of the rectal identity. In addition, cell division is necessary but not sufficient for this transdifferentiation event while the Wnt signaling plays distinct functions during the process including the selection of the daughter cell with a different fate, loss of the rectal identity and imposition of the specific neuronal subtype identity. We provide evidence that both the Wnt signaling and Y-to-PDA reprogramming factor SEM-4/SALL, SOX-2, CEH-6/POU act in parallel for the rectal identity erasure. Our results further support a model where antagonistic activities of SOX-2 and POP-1 and decreasing SOX-2 levels over time provide a timer for the acquisition of the final identity. In addition, the different levels of SOX-2 provide a mechanism for the integration of Wnt opposite dedifferentiation and re-differentiation functions during K-to-DVB transdifferentiation.

developmental biology↗

bioRxiv2019

PINK1-parkin-mediated mitophagy generates stereotyped somatic mosaicism of the mitochondrial genome

In multiple species, certain tissue types are prone to acquiring greater loads of mitochondrial genome (mtDNA) mutations relative to others, however the mechanisms that drive these heteroplasmy differences are unknown. We found that the conserved PTEN-induced putative kinase (PINK1/PINK-1) and the E3 ubiquitin-protein ligase parkin (PDR-1), which are required for mitochondrial autophagy (mitophagy), underlie stereotyped differences in heteroplasmy of a deleterious mitochondrial genome mutation ({Delta}mtDNA) between major somatic tissues types in Caenorhabditis elegans. We demonstrate that tissues prone to accumulating {Delta}mtDNA have lower mitophagy responses than those with low mutation levels, such as neurons. Moreover, we show that {Delta}mtDNA heteroplasmy increases when proteotoxic species that are associated with neurodegenerative disease and mitophagy inhibition are overexpressed in the nervous system. Together, these results suggest that PINK1 and parkin drive organism-wide patterns of heteroplasmy and provide evidence of a causal link between proteotoxicity, mitophagy, and mtDNA mutation levels in neurons.

cell biology↗