Overview

The Dorn Lab at Washington University investigates the role of mitochondrial dynamics (fusion, fission, trafficking) in disease.

Mitochondrial respiration produces ATP that powers most biological activity in multicellular organisms. To maintain respiratory fitness mitochondria self-identify for repair, transportation, replication or elimination. Outer mitochondrial membrane mitofusin (MFN) proteins are central regulators of these processes, comprising a communications interface between resident mitochondria and host cells, and maintaining homeostatic balance by directing individual organelles to different fate pathways based on current cellular or subcellular need. Thus, MFN-mediated mitochondrial fusion promotes organelle health via complementation-based repair of mitochondrial DNA and respiratory enzymes; MFN-directed mitochondrial transport through neuronal axons delivers healthy mitochondria to, and removes damaged mitochondria from, distal nerve endings; and MFN2 is a Parkin receptor that recruits cytosolic Parkin to damaged mitochondria for mitophagic elimination. For these reasons, modulation of MFN function is a central mechanism maintaining mitochondrial homeostasis in response to different physiological stressors. When mitofusin expression or activity is dysregulated, the resulting perturbations of these processes can provoke disease.

Among other activities, over the past half dozen years DornLab trainees discovered a novel mechanism for mitofusin activation involving conformational shifts, devised peptide and first in class small molecule mitofusin activators that “nudge” mitofusins into their active conformation, and developed pharmaceutically-acceptable mitofusin activators having potential clinical utility in mitochondrial cardiomyopathy and peripheral neuropathy.

Links for additional information about Dr Dorn:

http://www.harringtondiscovery.org/discoveries/gerald-w-dorn-ii

https://www.ahajournals.org/doi/epub/10.1161/CIRCRESAHA.115.308213

https://health.usf.edu/~/media/Files/Research/Research%20Day/Dorn_bio.ashx?la=en