Metalloendopeptidase OMA1-Activating transcription factor 4 signaling pathway (OMA1-ATF4)

The OMA1-ATF4 signaling pathway, also known as the mitochondrial integrated stress response (mtISR), is a critical mitonuclear communication axis that relays mitochondrial dysfunction to the nucleus [1, 2]. Upon mitochondrial stress, such as loss of membrane potential or proteotoxic stress, the inner mitochondrial membrane protease OMA1 is activated and cleaves the protein DELE1 [1, 3]. The resulting C-terminal fragment of DELE1 translocates to the cytosol, where it binds and activates the heme-regulated inhibitor (HRI) kinase [1, 6]. HRI then phosphorylates eIF2α, leading to the selective translation of the transcription factor ATF4, which orchestrates a gene expression program aimed at restoring homeostasis or, under persistent stress, inducing apoptosis [2, 10]. This pathway is a significant therapeutic target in oncology, where hyperactivation can trigger cell death in aggressive cancers like diffuse large B-cell lymphoma (DLBCL) [5, 9]. Conversely, in neurodegenerative and cardiovascular diseases, the pathway's modulation is being explored for potential cytoprotective effects [3, 4]. Small molecules like BTM-3566 act as OMA1 agonists to exploit this pathway for cancer therapy, while OMA1 inhibitors are being researched to mitigate tissue damage in ischemic and degenerative conditions [4, 5].

Other names

OMA1-DELE1-HRI-ATF4 axisMitochondrial integrated stress responsemtISROMA1-DELE1-HRI pathwayMitochondrial stress-induced ISR

Agonism of the OMA1 protease to trigger the DELE1-HRI-eIF2α-ATF4 signaling cascade, leading to integrated stress response activation and apoptosis.