Mafalda Escobar-Henriques

Institute for Genetics, CMMC

Research Areas

2
3

Mitochondrial Dynamics and Ubiquitin

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.

Research Focus

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.

Our Goals

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.

  • First, mitofusins are dynamin-related GTPase proteins, mostly consisting of soluble proteins known to perform fission events. Interestingly, it is strikingly unclear how lipid-embedded versions of dynamin-related proteins (DRPs) promote membrane fusion. To approach this question, we investigate the different steps and components required, both in vivo and in reconstituted systems.
     
  • Second, the importance of mitofusins goes clearly beyond membrane fusion. We are currently studying their quality-control functions, e.g. in proteostasis, in the clearance of defective mitochondria, called mitophagy, and in programmed cell death.
     
  • Third, ubiquitin is paramount for stress adaptation and cellular health. We focus on deciphering the mechanistic features behind stress management by ubiquitin and CexUb. This includes cellular responses to transcription, translation, or post-translational defects. We globally aim at identifying biomarkers and exploring therapeutic strategies.

Key Publications


  1. Anton V, Buntenbroich I, Simões T, Joaquim M, Müller L, Büttner R, Odenthal M, Hoppe T and Escobar-Henriques M (2023). E4 ubiquitin ligase promotes mitofusin turnover and mitochondrial stress response. Molecular Cell, 49:487-498. DOI: 10.1016/j.molcel.2012.12.003 (Open access)
     
  2. Buntenbroich I, Anton V, Perez-Hernandez D, Simões T, Babatz Gaedke F, Schauss A, Dittmar G, Riemer J and Escobar-Henriques M (2023). Novel docking and stability steps in mitochondrial fusion highlight the proteasome as potential therapeutic target. iScience, Jun 7;26(7):107014. DOI: 10.1016/j.isci.2023.107014 (Open access).
     
  3. Joaquim M and Escobar-Henriques M (2020). Role of mitofusins and mitophagy in life or death decisions.  Front. Cell Dev. Biol., 8:572182. DOI: 10.3389/fcell.2020.572182 (Open access).
     
  4. Simões T, Schuster R, den Brave F and Escobar-Henriques M (2018). Cdc48 regulates a deubiquitylase cascade critical for mitochondrial fusion. Elife. Jan 8 e30015. DOI: 10.7554/eLife.30015 (Open access)
     
  5. Anton F, Dittmar G, Langer T and Escobar-Henriques M (2013). Two deubiquitylases act on mitofusin and regulate mitochondrial fusion along independent pathways. Molecular Cell, 49 487-498. DOI: 10.1016/j.molcel.2012.12.003 (Open access)

Research Areas

2
3