Temporal transcriptional regulation of mitochondrial morphology primes activity-dependent circuit connectivity

Iryna Mohylyak, Maheva Andriatsilavo, Mercedes Bengochea, Carlos Pascual-Caro, Noemi Asfogo, Sara Fonseca-Topp, Natasha Danda, Marlene Cassar, Corentine Marie, Zeynep Kalender Atak, Maxime Waegeneer, Stein Aerts, Olga Corti, Jaime Juan-Sanz and Bassem A. Hassan ()
Additional contact information
Iryna Mohylyak: Hôpital Pitié-Salpêtrière
Maheva Andriatsilavo: Hôpital Pitié-Salpêtrière
Mercedes Bengochea: Hôpital Pitié-Salpêtrière
Carlos Pascual-Caro: Hôpital Pitié-Salpêtrière
Noemi Asfogo: Hôpital Pitié-Salpêtrière
Sara Fonseca-Topp: Hôpital Pitié-Salpêtrière
Natasha Danda: Hôpital Pitié-Salpêtrière
Marlene Cassar: Hôpital Pitié-Salpêtrière
Corentine Marie: Hôpital Pitié-Salpêtrière
Zeynep Kalender Atak: Center for Brain and Disease Research – VIB-KU Leuven
Maxime Waegeneer: Center for Brain and Disease Research – VIB-KU Leuven
Stein Aerts: Center for Brain and Disease Research – VIB-KU Leuven
Olga Corti: Hôpital Pitié-Salpêtrière
Jaime Juan-Sanz: Hôpital Pitié-Salpêtrière
Bassem A. Hassan: Hôpital Pitié-Salpêtrière

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Synaptic connectivity during development is known to require rapid local regulation of axonal organelles. Whether this fundamental and conserved aspect of neuronal cell biology is orchestrated by a dedicated developmental program is unknown. We hypothesized that developmental transcription factors regulate critical parameters of organelle structure and function which contribute to circuit wiring. We combined cell type-specific transcriptomics with a genetic screen to discover such factors. We identified Drosophila CG7101, which we rename mitochondrial integrity regulator of neuronal architecture (Mirana), as a temporal developmental regulator of neuronal mitochondrial quality control genes, including Pink1. Remarkably, a brief developmental downregulation of either Mirana or Pink1 suffices to cause long-lasting changes in mitochondrial morphology and abrogates neuronal connectivity which can be rescued by Pink1 expression. We show that Mirana has functional homology to the mammalian transcription factor TZAP whose loss leads to changes in mitochondrial function and reduced neurotransmitter release in hippocampal neurons. Our findings establish temporal developmental transcriptional regulation of mitochondrial morphology as a prerequisite for the priming and maintenance of activity-dependent synaptic connectivity.

Date: 2025
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DOI: 10.1038/s41467-025-62908-2

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