Michelle Fry @myfry.bsky.social · 02/10/202610/ 🧵 In short: the TCA cycle and OXPHOS aren't just sequential pathways. They can be physically organized and functionally coupled within a single molecular machine. 011
Michelle Fry @myfry.bsky.social · 02/10/20269/Thanks to the @hhmi-science.bsky.social Emerging Pathogens Initiative, @jcchildsfund.bsky.social , and Mark and Lisa Schwartz for funding our MitoTOL work. 110
Michelle Fry @myfry.bsky.social · 02/10/20268/ This work would not have been possible without my postdoc mentor @lukechao.bsky.social, our amazing collaborators (Vamsi Mootha, Jon Stefely, Bridget Luce, Michael Chen, Felicia Deng, Tiana Issa, and many more). The people were the best part of this collaboration. 100
Michelle Fry @myfry.bsky.social · 02/10/20267/ This work shows what these inventories make possible. They let us ask not just which proteins are in mitochondria, but how conserved mitochondrial machines have been rewired, expanded, and repurposed across eukaryotic evolution? 121
Michelle Fry @myfry.bsky.social · 02/10/20266/This work is part of a much larger effort by the MitoCarta Tree of Life (MitoTOL) Consortium to experimentally defined mitochondrial proteomes for 5 protist pathogens and Arabidopsis. www.cell.com/consortium/m.... Data: mitocarta.orgcell.comMitoCarta Tree of Life consortium: Cell Press 122
Michelle Fry @myfry.bsky.social · 02/10/20265/ This changes how we might think about metabolism and OXPHOS. They don’t have to be pathways connected only through shared cofactors and substrates. Mitochondria can organize enzymes into assemblies that could couple local metabolic chemistry to OXPHOS machinery. 110
Michelle Fry @myfry.bsky.social · 02/10/20264/ And this isn't just a structural connection. Within ATP synthase, MDH remains active, its working substrate concentration range expands, and ATP and ADP differentially impact its activity. This suggests the architecture results in functional consequences. 100
Michelle Fry @myfry.bsky.social · 02/10/20263/ The MDH dimer docks by wrapping an N-terminal extension around a small lineage-specific subunit we dubbed MASA (MDH-ATP synthase adapter). It's a beautiful example of lineage-specific innovation being incorporated directly into a conserved molecular machine. 100
Michelle Fry @myfry.bsky.social · 02/10/20262/ The enzyme is malate dehydrogenase (MDH), a core TCA-cycle enzyme. By imaging unenriched and unpurified mitochondrial lysate, we resolved the cryo-EM structure of Acanthamoeba ATP synthase and found an MDH dimer integrated into its peripheral stalk. 120
Michelle Fry @myfry.bsky.social · 02/10/20261/ 🧵 Two classic mitochondrial pathways the TCA cycle and OXPHOS are taught as linked but distinct pathways. I’m happy to share our new work out in @cp-cell.bsky.social showing that in Acanthamoeba they're physically linked—with a TCA enzyme incorporated in ATP synthase. www.cell.com/cell/fulltex...cell.comAcanthamoeba ATP synthase structure reveals the TCA cycle is tethered to OXPHOSAcanthamoeba castellanii, a pathogenic amoeba, belongs to an evolutionary branch distinctly removed from humans and fungi. Cryo-EM of the organism’s ATP synthase enzyme using raw mitochondrial lysates... 15326
Reposted by Michelle FryJane Coffin Childs Fund for Medical Research @jcchildsfund.bsky.social · 19/05/2026Jane Coffin Childs Fellow Dr. Michelle Fry studies perhaps the most iconic organelle of the cell, the mitochondria. Almost everyone knows that mitochondria are the powerhouse of the cell, but few know they are essential for other functions like respiration and ... @myfry.bsky.social 1/ 192
Michelle Fry @myfry.bsky.social · 22/11/2024This is such a great idea! Thank you for making this. Could you please add me?✋ 111
Michelle Fry @myfry.bsky.social · 14/11/20246/ Many thanks to Chen and Tom for inviting us to collaborate and expand on our shared interest in how Opa1 perturbations drive changes in mitochondrial ultrastructure. 020
Michelle Fry @myfry.bsky.social · 03/10/20245/ Our findings bring us closer to understanding the molecular mechanisms behind ADOA and open new avenues for developing targeted therapies to prevent neurodegeneration. 110
Michelle Fry @myfry.bsky.social · 03/10/20244/ We've identified Sarm1 as a key driver of RGC degeneration in our mouse model. Remarkably, knocking out SARM1 nearly completely suppresses these degeneration phenotypes, offering new hope for potential therapies. 120
Michelle Fry @myfry.bsky.social · 03/10/20243/ Using cryo-ET, we quantified architectural changes in mitochondrial ultrastructure, giving us detailed insights into how this pathogenic OPA1 mutation affect mitochondrial integrity at the nanoscale level. 110
Michelle Fry @myfry.bsky.social · 03/10/20242/ Our novel mouse model carrying the Opa1R290Q/+ allele recapitulates key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC function. 120
Michelle Fry @myfry.bsky.social · 03/10/20241/ ADOA, a common inherited optic neuropathy, leads to RGC degeneration and vision loss. It's primarily caused by mutations in the OPA1 gene, a key player in mitochondrial inner membrane dynamics. 110
Michelle Fry @myfry.bsky.social · 03/10/2024Excited to share our collaborative work characterizing a pathogenic mutation in Opa1 found in ADOA patients that began when Tom Schwarz @BostonChildrens presented a seminar @MGHMolBio biorxiv.org/content/10.1... @lukechao.bsky.socialbiorxiv.orgLoss of SARM1 protects against retinal ganglion cell degeneration in Autosomal Dominant Optic AtrophyAutosomal Dominant Optic Atrophy (ADOA), the most prevalent inherited optic neuropathy, leads to retinal ganglion cell (RGC) degeneration and vision loss. ADOA is primarily caused by mutations in the ... 171
Michelle Fry @myfry.bsky.social · 03/10/20244/ We've identified Sarm1 as a key driver of RGC degeneration in our mouse model. Remarkably, knocking out SARM1 nearly completely suppresses these degeneration phenotypes, offering new hope for potential therapies. 010
Michelle Fry @myfry.bsky.social · 03/10/20243/ Using cryo-ET, we quantified architectural changes in mitochondrial ultrastructure, giving us detailed insights into how this pathogenic OPA1 mutation affect mitochondrial integrity at the nanoscale level. 100
Michelle Fry @myfry.bsky.social · 03/10/20242/ Our novel mouse model carrying the Opa1R290Q/+ allele recapitulates key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC function. 120
Michelle Fry @myfry.bsky.social · 03/10/20241/ ADOA, a common inherited optic neuropathy, leads to RGC degeneration and vision loss. It's primarily caused by mutations in the OPA1 gene, a key player in mitochondrial inner membrane dynamics. 100
