Role of Mitochondrial Metabolism on zebrafish heart regeneration
Description: 1.SummaryBackground: In contrast to humans, zebrafish have the capacity to regrow their heart upon injury. Understanding the mechanisms of this natural capacity of organ regeneration is of great scientific interest. Indeed, studies in the mouse showed that the regenerative capacity of zebrafish also observed to a limited degree in mammals, namely during a short postnatal period. Upon cardiac injury, an initial inflammatory response is followed by the activation of fibroblast that deposit extracellular matrix. Neoangiogenesis allows the establishment of new vessels and this is followed by regrowth of lost myocardium. In zebrafish, myocardial regeneration is based on cell cycle reentry of cardiomyocytes (CMs). To allow proliferation, CMs have been shown to undergo a metabolic switch from oxidative phosphorylation (OXPHOS) to glycolysis. Other reports are suggestive of a far more complex metabolic rewiring during regeneration and showed that differential mitochondrial substrate utilization regulates cell cycle progression. The OXPHOS chain is comprised of five highly conserved protein complexes (CI to CV) that can also assemble into Supercomplexes (SC). SC assembly is facilitated through SC assembly factors in zebrafish but also mice and humans. We previously showed that loss of assembly factor cox7a2l alters SC formation and consequently affect organism physiology in the zebrafish. Here we aim to explore the role of further member of the cox7a family on metabolic adaptation and injury response.Hypothesis: Changes in Super complex assembly affects heart regeneration in a highly specific manner. Objectives: Mi-Heart will explore how organismal and cellular metabolism affects regenerative capacity of the heart, i.e. if and how changes in the assembly of the mitochondrial OXPHOS Complexes affects heart regeneration. Aims: We will study how mutations of different OXPHOS assembly factors affect metabolic rewiring and how this impacts heart regeneration using the zebrafish animal model. We will examine the underlying mechanisms through which loss of assembly factors affect mitochondrial architecture and how the altered metabolism affects gene expression by altering epigenetic marks.Methodology: We will study why cox7a1 affects heart regeneration and if other members of the cox7a family of supercomplex assembly factors also have a role during this process. We will generate single and compound null mutant zebrafish lines as well as a myocardial specific tissue-specific null mutant line. We will study SC assembly in gain and loss of function models of the cox7a family of assembly factors using Blue Native Gel Electrophoresis and methods to assess mitochondrial respiration such as Seahorse. We will study the effect on heart regeneration using immunostainings for immune response markers, neonagiogenesis, cell proliferation and fibrosis regression and an AI-based imaging processing suite. We will use Electron Microscopy to study mitochondrial morphology including cristae formation and investigate the effects on metabolic rewiring using NMR-Spectroscopy and Seahorse Metabolic imaging. Furthermore, we will assess a possible link between alterations in SC assembly and Ca-homeostasis using Ca-sensor lines. Expected results and impact This work will dissect the role of SC assembly on cardiac injury response and how mitochondrial metabolism rewires overall metabolic activity that ultimately controls a regenerative response in the myocardium. The herein developed materials and methods including new genetically engineered lines, epigenomic datasets will also be of great use for further studies in the context of organ regeneration and beyond. Given the conserved role of cox7a2l on SC assembly and regulation of organism physiology, we expect our studies in the zebrafish on further cox7a family members have a broad impact and be of general relevance to understand these genes’ function in organ physiology and stress response.
Amount: CHF 767,000
Funding type: research
Funder scheme: Project funding
Start date: 2025-03-01
End date: 2029-02-28
Investigator: Mercader Huber, Nadia
Institution: University of Berne – BE
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 1
Funder award ID: 10002235
OpenAlex ID: G8162915701