Our Technology
Shapeshifting mitochondria
Mitochondria are dynamic organelles whose morphology is intimately linked to energy metabolism, quality-controls and stress responses. A delicate balance of fission and fusion events dictates cell fate, determining whether damaged mitochondria are recycled (mitophagy) or entire cells are eliminated (apoptosis).
Alavi 2019 Int J Cancer
A central regulator in this process is the inner membrane protease OMA1. In stressed cells, OMA1 cleaves the membrane-shaping protein OPA1, 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 multifunctional protease
Reciprocal hydrolysis of OMA1 and the i-AAA protease regulates mitochondrial capacity and signal apoptosis via OPA1 cleavage.
DELE1 cleavage stalls overall protein synthesis and drives the expression of chaperones in the context of the integrated stress response.
OMA1 in concert with PARL coordinates mitochondrial fission via PGAM5 and removes misfolded or misrouted proteins from the inner membrane (e.g., PINK1).
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
712 North's core technology is the Luke-S1 assay, a powerful, proprietary, high-throughput drug discovery engine. This bioluminescence reporter is designed to screen for small molecule modulators of OMA1 activity. Because the assay's signal is inversely proportional to OMA1 activity, it is uniquely efficient at identifying both inhibitors (potential treatments for neurodegeneration) and activators (potential treatments for cancer).