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Metabolic regulation of mitochondrial morphology

Periodic Reporting for period 2 - Mitomorphosis (Metabolic regulation of mitochondrial morphology)

Reporting period: 2018-10-01 to 2020-03-31

The research focus of the lab is to understand the complex interplay of mitochondrial dynamics and metabolism in health and disease. Mitochondria are essential organelles whose morphology varies tremendously across cell types and tissues. Balanced fusion and fission events shape mitochondria to meet metabolic demands and to ensure removal of damaged organelles. The dynamism of mitochondria is highlighted by the dramatic changes in morphology they undergo in response to metabolic inputs. Mitochondrial fragmentation occurs in response to nutrient excess and cellular dysfunction and has been observed in cardiovascular and neuromuscular disorders, cancer, and obesity. The morphology of mitochondria is inextricably linked to its many essential functions in the cell and we are interested in understanding the relationship between mitochondrial shape changes and metabolism in the context of acquired and inborn human diseases Objectives. Mitochondria are essential organelles whose morphology varies tremendously across cell types. The physiological relevance of mitochondrial morphology and the mechanisms that regulate mitochondrial dynamics in vivo are poorly understood.

We seek to
• Identify the metabolic signals that balance mitochondrial fusion and fission
• Define the molecular mechanisms of stress-induced fission
• Design strategies aimed at re-balancing mitochondrial dynamics in vivo
• Translate our experimental findings to acquired and inborn human diseases

Our research strategy builds upon frontier science in the areas of cell biology and biochemistry of mitochondria. We apply this knowledge to preclinical animal models and cellular models derived from patient biopsies to address fundamental translational knowledge gaps in rare genetic diseases of metabolism as well as common acquired age-associated diseases including heart disease, diabetes, and cancer.
We have generated an automated cellular imaging pipeline able to quantify mitochondrial morphology at the single-cell level in a high throughput manner. We have applied this novel imaging pipeline to screen for genes that are essential for mitochondrial fission and fusion in human cells and have also used it to decipher the mechanisms of mitochondrial morphology maintenance in cells from patients with mitochondrial genetic diseases. We have gained unexpected insights into the cellular and mitochondrial pathways that can regulate mitochondrial morphology in both health and disease. We have generated transgenic mouse models for a novel mitochondrial fission factor, allowing us to gain insights into its physiological relevance in various tissues that are commonly affected in mitochondrial genetic diseases.
We have devised novel methods to perform unbiased quantification of mitochondrial morphology, cell growth, cell death (apoptosis), and mitophagy in a high throughput fashion. We have combined this approach with siRNA screening and have been able to uncover novel regulators of mitochondrial morphology that are able to rebalance mitochondrial morphology in cells from patients with mitochondrial genetic disease. We expect to describe the molecular mechanisms associated with this phenotypic rescue and determine whether other mitochondrial functions besides mitochondrial morphology are also rescued. In other words, we expect to determine whether mitochondrial morphology is relevant for mitochondrial function and cellular health. In addition we have specifically probed the function of an inner membrane fission factor both in vitro and in vivo and have found that its removal both protects against liver disease but is also essential for cardiac function. By the end of the project, we expect to understand its mode of action in these tissues under basal and stress conditions.