Reversible induction of mitophagy by an optogenetic bimodular system

Pasquale D’Acunzo, Flavie Strappazzon, Ignazio Caruana, Giacomo Meneghetti, Anthea Di Rita, Luca Simula, Gerrit Weber, Francesca Del Bufalo, Luisa Dalla Valle, Silvia Campello, Franco Locatelli and Francesco Cecconi ()
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Pasquale D’Acunzo: Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital
Flavie Strappazzon: IRCCS Fondazione Santa Lucia
Ignazio Caruana: Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital
Giacomo Meneghetti: University of Padova
Anthea Di Rita: IRCCS Fondazione Santa Lucia
Luca Simula: Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital
Gerrit Weber: Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital
Francesca Del Bufalo: Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital
Luisa Dalla Valle: University of Padova
Silvia Campello: IRCCS Fondazione Santa Lucia
Franco Locatelli: Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital
Francesco Cecconi: Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Autophagy-mediated degradation of mitochondria (mitophagy) is a key process in cellular quality control. Although mitophagy impairment is involved in several patho-physiological conditions, valuable methods to induce mitophagy with low toxicity in vivo are still lacking. Herein, we describe a new optogenetic tool to stimulate mitophagy, based on light-dependent recruitment of pro-autophagy protein AMBRA1 to mitochondrial surface. Upon illumination, AMBRA1-RFP-sspB is efficiently relocated from the cytosol to mitochondria, where it reversibly mediates mito-aggresome formation and reduction of mitochondrial mass. Finally, as a proof of concept of the biomedical relevance of this method, we induced mitophagy in an in vitro model of neurotoxicity, fully preventing cell death, as well as in human T lymphocytes and in zebrafish in vivo. Given the unique features of this tool, we think it may turn out to be very useful for a wide range of both therapeutic and research applications.

Date: 2019
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DOI: 10.1038/s41467-019-09487-1

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