In the Mitomorphosis project, we developed new first-in-kind tools and strategies applied to patient-derived cells and preclinical animal models of disease in order to advance our molecular and cellular understanding of mitochondrial dynamics, allowing us to advance the state of the art.
To be able to measure mitochondrial morphology accurately, rapidly, and unbiasedly in cells, we generated an automated cellular imaging pipeline able that was able to quantify mitochondrial morphology using supervised machine learning, enabling us to define mitochondrial morphology at the single-cell level in a high throughput manner. We have applied this novel imaging pipeline to test all the known mitochondrial proteins (>1500) and identify the genes required for mitochondrial fission and fusion in human cells. By applying this technology to patient-derived cells that suffered from defects in mitochondrial morphology, we were able to identify 91 new targets able to restore normal mitochondrial shape. This work was shared as a pre-print and published in the journal EMBO Molecular Medicine (Cretin et al 2021). The work was presented in several international scientific meetings and invited presentations and the overall strategy was discussed on French radio and press releases.
The tools we established were used to screen patient-derived fibroblasts, allowing us to gain unexpected insights into the cellular and mitochondrial pathways caused by new disease-causing mutations in mitochondrial genes, which led to publications in the journals Molecular Genetics and Metabolism, Journal of Experimental Medicine, and Brain.
We also generated transgenic mouse models for a novel mitochondrial fission factor, allowing us to gain insights into its physiological relevance in various tissues that are commonly affected in mitochondrial genetic diseases. In the heart, we discovered that this protein plays important roles for mitochondrial healthy by maintaining the integrity of the inner membrane, specifically important for the resilience and bioenergetic efficiency of mitochondria. In its absence, mice succumbed to heart failure and middle-aged death, highlighting the importance of this gene. This work was published in the journal Nature Communications (Donnarumma et al. 2022), was shared as a referred pre-print and was presented in several international and national scientific meetings.
In the liver, we discovered this protein to be a key regulator of mitochondrial and metabolic activity. Its deletion in hepatocytes is physiologically benign in mice yet leads to the upregulation of oxidative phosphorylation complexes and mitochondrial respiration. Consequently, hepatocyte-specific knockout mice are protected against high fat diet-induced fatty liver disease, metabolic dysregulation, and liver cell death. This study uncovered novel functions of this protein in the liver, positioning it as an unexpected regulator of mitochondrial bioenergetics and therapeutic target for fatty liver disease, which is a disease caused by an imbalance between nutrient delivery and metabolism in the liver. This work is in preparation for publication and pre-print dissemination and has been presented at international scientific meetings and seminars.
