Mitochondria exist as a dynamic reticuluum in cells, regulated by opposing fusion and fission reactions. We performed in vitro reconstitution to understand regulation of mitochondrial inner-membrane fusion by Opa1 (Ge et al., 2020). These studies revealed a rheostat framework for how levels of processing regulate fusion. We've collaborated with Tom Schwartz's group (Boston Children’s) to understand Opa1 mutants in Dominant Optic Atrophy. This collaboration revealed a stalled intermediate state of fusion where the outer membranes have merged, but the inner-membranes are distinct (Ding et al., 2025). We have also used Cross-Linking Mass Spectrometry (XL-MS) and AlphaFold modeling to characterize interaction interfaces between SLC25A46 and the mitochondrial membrane fusogens Opa1 and Mfn2 (Boopathy et al., 2024). Some of our current efforts focus on leveraging these mechanistic insights, to engineer fusion as a means to delivery diverse cargos.

The mitochondrial inner membrane (IMM) is an elaborately sculpted membrane iconic in cell biology. Its characteristic folds (cristae) dramatically expand surface area and create compartments that concentrate the machinery of oxidative phosphorylation. How cristae are built, maintained, and remodeled in response to cellular signals are key questions for our lab. We have analyzed how Opa1 processing results in shifts the population of cristae morphologies (Fry, Navarro et al., 2024). We have also used Ancestral Sequence Reconstruction to understand how Mic60 — a core component of the MICOS complex — has evolved to support respiration across species (Benning, Bell, Nguyen et al., 2025). We are currently fascinated by the extraordinary morphological diversity of mitochondria: their unusual cristae geometries, their distinct inner membrane protein complements, and what these variations reveal about the design logic of respiration and metabolism.

We are excited by discovery-oriented structural biology of endogenous assemblies imaged directly from crude or minimally processed lysates, and near-native imaging organisms (and their innards) that have not been difficult to culture via classical approaches. There is much to explore!