Our Technology
Shapeshifting mitochondria
Mitochondria are interconnected. A delicate balance of fission and fusion events intimately linked to energy metabolism, quality-controls and stress responses, determines their morphology.
Mitochondria are dynamic. They constantly divide and merge singling out damaged mitochondria and recycling them through mitochondrial autophagy (mitophagy).
Severely damaged cells, on the other hand, are eliminated through apoptosis, which also involves mitochondrial breakdown and cell death signaling.
Alavi 2019 Int J Cancer
The mechanisms that determine whether individual mitochondria or entire cells are targeted for recycling remain unclear. One potential pathway involves the mitochondrial proteins OPA1 and OMA1, specifically the cleavage of OPA1 by the OMA1 protease, a hallmark event in both mitophagy and apoptosis.
OPA1—a membrane-shaping GTPase
OPA1 coats membranes like many other dynamin-family proteins. OPA1 (L-OPA1) possesses a membrane anchor for this purpose.
The OMA1 protease cleaves L-OPA1 in stressed cells releasing S-OPA1 from the inner membrane.
Both OMA1 inhibition and ectopic OPA1 expression prevent apoptosis. OPA1 thus plays a critical role in apoptosis beyond providing merely structural support.
Alavi 2021 BBA – Proteins Proteom
OMA1—a protease with limited substrates
The inner membrane proteases orchestrate complex functions. Reciprocal hydrolysis of OMA1 and the i-AAA protease regulate mitochondrial capacity and promote apoptosis via OPA1.
OMA1 cleaves DELE1 in the context of the integrated stress response reducing overall protein synthesis and increasing the expression of chaperones.
OMA1 in concert with PARL coordinate mitochondrial fission via PGAM5 and remove misrouted PINK1 from the inner membrane.
Alavi & Fuhrmann 2013 Mol Neurodegen
712 North's core technology is built around a powerful drug discovery engine: the Luke-S1 assay.
Alavi 2021 ACS Chem Biol
Luke-S1 is a powerful high-throughput drug screening assay for OMA1 modulators. The proprietary bioluminescence reporter inversely correlates with OMA1 activity and is suitable for the identification of both inhibitors and activators.