Project description
A closer look at mitochondrial quality control mysteries
In the world of cellular biology, maintaining mitochondrial health is crucial for cellular functions such as bioenergetics, metabolism, and cell regulation. Yet, the triggers for quality control processes like mitophagy remain elusive, despite their critical roles. Addressing this challenge head-on, the ERC-funded INTEGRATE project pioneers advanced tools for real-time imaging of protein aggregation within mitochondrial sub-compartments. By uncovering how these aggregates initiate distinct responses based on their location (whether in the matrix or intermembrane space), the project will decode the rules governing mitochondrial quality control. This breakthrough promises profound insights into cellular and mitochondrial biology, offering potential applications in ageing and pathological conditions where maintaining mitochondrial health is paramount.
Objective
Quality control processes maintain mitochondrial health, enabling cellular functions such as bioenergetics, metabolism, Ca2+ signaling, and cell death regulation. Mitochondrial proteases, unfolded protein response, asymmetric fission, vesicle shedding, and mitophagy all contribute to organelle quality. However, the specific triggers for these processes remain unclear. While unfolded protein accumulation appears to be a common trigger, the mechanism by which it initiates diverse responses remains uncertain.
To investigate this question, we developed advanced tools for real-time imaging of protein aggregation in mitochondrial subcompartments. Aggregates in the matrix and intermembrane space induce mitochondrial fission and elicit distinct functional responses based on their location. Live imaging revealed that intermembrane space aggregates initially seed in the mitochondrial midzone and then sort through transient side-by-side fusion with neighboring mitochondria. In the matrix, aggregates seed at one pole and are selectively sorted to daughter mitochondria through asymmetric fission. Our preliminary experiments unveiled an early seeding and sorting process of protein aggregates according to their intramitochondrial location.
In the INTEGRATE project, we aim to comprehensively understand the underlying principles and consequences of this process. By combining advanced imaging techniques, omics analysis, biochemistry, functional assays, and unbiased screenings, we will decipher the rules governing aggregate formation, seeding, sorting, cellular fate, and response in various mitochondrial subcompartments.
INTEGRATE seeks to establish the occurrence and downstream responses of this newly discovered early phase of mitochondrial quality control. Clarifying this fundamental mechanism will provide insights into mitochondrial and cell biology, with significant implications for pathological conditions and aging, where mitochondrial quality control is compromised.
Fields of science
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
35122 Padova
Italy