Mark A. Herzik
Developing hybrid methods to understand dynamic mitochondrial protein assemblies
Maintaining mitochondrial integrity is critical for human cell physiology as numerous processes – including the biosynthesis of various cellular building blocks – are highly dependent on mitochondrial proteins and their functions. Mitochondria play crucial functions in cellular signaling pathways, quality control, and programmed cell death, and not surprisingly, mitochondrial dysfunction is associated with a large number of human disorders, including type 2 diabetes, neurodegenerative diseases, and cancers.
Critical to mitochondrial function is its dual-membrane architecture, which provides appropriate microenvironments that facilitate specific metabolic functions and allow for otherwise incompatible processes to occur simultaneously inside the cell. However, the segregation of these components within mitochondria require the coordinated efforts of several protein complexes to ensure proper trafficking of small molecules and proteins into mitochondria and between the various compartments. Indeed, although human mitochondria require the coordinated functions of nearly 1500 unique proteins, 99% of those proteins must be imported into mitochondria, then processed, folded, and sorted in their respective compartments. With the support of the Searle Scholars Program, my group will use targeted biochemical approaches and innovative cryogenic electron microscopy (cryo-EM) technologies to determine the three-dimensional architecture of the major mitochondrial protein biogenesis and transport machinery. To better understand these machines’ dynamics and function, we will use novel modeling strategies to tease out new information on conformational heterogeneity from massive cryo-EM datasets. By unraveling how these cellular machines operate, we hope to lay a foundation for understanding the biogenesis of mitochondrial proteins at the atomic level.