Grant: Discovery Grants Program - Individual

Mitochondria are a central metabolic hub. As a consequence, they play a crucial role in cellular functions ranging from maintenance of stem cells to cell growth and differentiation. Mitochondrial activity thus needs to be tightly controlled through the modulation of their energetic output and modification of their structure. This occurs through changes in mitochondrial length, reorganisation of mitochondrial cristae, the folds of the mitochondrial inner membrane, and interaction with the endoplasmic reticulum (ER). Mitochondria form interconnected networks that are constantly changing through mitochondrial fusion and fission. For example, amino acid starvation causes an increase in mitochondrial length which is required to maintain the levels of cellular energy and cell survival. To follow up on these studies, we recently developed a novel algorithm to measure mitochondrial length and connectivity (mitochondrial branch sites). Using this algorithm, we showed that increased in mitochondrial connectivity is a key feature of nutrient starvation, contrary to elongation which is restricted to amino acid starvation. This supports the novel idea that mitochondrial length and connectivity are two independent determinants of mitochondrial function. We thus hypothesize that mitochondrial network connectivity is a key determinant of mitochondrial function required for cellular adaptation to changes in nutrient availability. We will: Aim 1. Define the link between mitochondrial connectivity and cristae structure. Mitochondrial structure and function are linked but the underlying mechanisms poorly understood. We will thus determine how changes in mitochondrial connectivity affect cristae structure and mitochondrial activity in the context of changing nutrient availability. Aim 2. Define the role of the cytoskeleton in regulating mitochondrial connectivity and activity. We will determine the role of both microtubules and the actin cytoskeleton in the regulation of mitochondrial connectivity and cristae structure. Aim 3. Define the role of ER-mitochondria contact sites in the coordination of mitochondrial connectivity and activity. ER-mitochondria contact sites control mitochondria fission and transfer of metabolites between the two organelles. We will thus determine the effect of nutrient starvation on ER-mitochondria contact sites. We will then define role of ER-mitochondria contact sites in the regulation of mitochondrial connectivity. Mitochondrial dynamics control cell fate by regulating key cellular functions. The mechanisms controlling mitochondrial structure and activity in the context of changing nutrient conditions, and their consequences on cell fate, are only partially understood. These experiments will thus provide much needed insights into the processes regulating mitochondrial architecture and activity.