Principal Investigator
Mitochondria are dynamic organelles of outmost importance for cellular quality control, key in neurodegeneration and metabolic diseases. We study ubiquitin-dependent mechanisms regulating mitochondrial homeostasis and cellular stress responses.
We focus on studying the mechanisms allowing tailored and coordinated adaptations of mitochondrial dynamics. Moreover, we investigate how novel forms of ubiquitin regulate stress responses and impact cellular survival, in concert with the ubiquitin proteasome system (UPS) and the autophagic machinery. Our research is strongly based on cell biology and biochemical studies of organellar morphology, mainly of mitochondria, and integration into protein translation, folding and turnover events.
Mitofusins are located at the mitochondrial surface, which allows them to sense and respond to many different stimuli.This impinges on mitochondrial morphological adaptations and cellular performance. We have recently reported on a mechanism that allows these many different signals to converge into a common cellular pathway, characterized by a ubiquitin-dependent proteolytic stress response. It involves the E4 activity of the ubiquitin ligase Ufd2/UBE4B, which extends ubiquitin chains on mitofusins, promoting their proteasomal turnover (Fig. 2). This mechanism modulates mitochondrial functionality and may be particularly relevant in disease
Mitochondria are biosynthetic hubs and multifold key players, e.g. in bioenergetics, redox signaling, and stress responses. Mitochondrial dysfunction underlies the development of many diseases and is a hallmark of ageing. The plastic capacity of mitochondria, enabled by fusion and fission events, provides adaptability capacities. Mitofusins are fusion factors, whose defects cause the peripheral neuropathy Charcot-Marie-Tooth Type 2A (CMT2A) and affect the pathogenesis of many common age-related diseases, including Non-Alcoholic Fatty Liver Disease (NAFLD) (Fig. 1). We found that the post-translational modifier ubiquitin regulates mitofusins, both in health and disease states. Ubiquitylation of mitofusins can either promote mitochondrial fusion or drive mitochondrial fragmentation, in response to proteotoxic stress or metabolic changes.
Our goal is to unveil the molecular bases allowing ubiquitin to safeguard mitochondria under stress. We wish to transform the relevance of these mechanisms into therapeutic options, e.g. for neurodegenerative and obesity-linked diseases.
Understanding how ubiquitylation of mitochondrial proteins actively controls mitochondrial morphology is at the heart of our research. We are particularly interested in the mitochondrial fusion factors, called mitofusins, and in a novel form of ubiquitin, called CexUb, that we recently identified.
Our main research projects address basic research questions and disease-relevant problems. We use yeast, worms, tissue culture and patient sample material. This is possible thanks to the highly collaborative CECAD environment.
Our long-term purpose is transferring the basic molecular mechanisms of mitochondrial fusion into therapeutic targets. This concerns diseases associated with mitofusin impairment and with deficient ubiquitin-dependent stress-responses. They comprise neurodegeneration, metabolic defects, and cancer. Currently, we focus on three main research areas.
Principal Investigator