Mitochondria, Fueling a Novel Extracellular Vesicle and Shaping the Heart

Abstract

Mitochondria are dynamic organelles that influence cellular processes beyond energy production. My dissertation explores two aspects of mitochondrial biology: the characterization of blebbisomes, a novel class of extracellular vesicles (EVs) containing functional mitochondria, and the role of mitochondrial dynamics in cardiac myocyte development. Blebbisomes are large EVs (up to 20 µm) with continuous membrane blebbing, released via a unique, myosin IIB-dependent process independent of the ESCRT-III complex. They can initiate apoptosis autonomously and contain immune checkpoint inhibitors like HLA-E, VISTA, and PD-L2, suggesting roles in immune evasion and intercellular communication. In cardiac myocytes, disrupting mitochondrial fission through DRP1 knockdown resulted in hyperfused mitochondria and impaired sarcomere assembly, resembling dilated cardiomyopathy. Conversely, MFN2 knockdown, inhibiting mitochondrial fusion, caused mitochondrial fragmentation and enhanced myofibril formation. Using DeAct plasmids to selectively disassemble actin on mitochondria rescued these defects, indicating actin’s critical role in coordinating mitochondrial dynamics and sarcomere formation. Together, these findings demonstrate that mitochondria actively shape cellular organization and communication, with implications for understanding cardiomyopathy, immune regulation, and disease progression.