Apoptosis repressor that blocks multiple modes of cell death. Inhibits extrinsic apoptotic pathways through two different ways. Firstly by interacting with FAS and FADD upon FAS activation blocking death-inducing signaling complex (DISC) assembly (By similarity). Secondly by interacting with CASP8 in a mitochondria localization- and phosphorylation-dependent manner, limiting the amount of soluble CASP8 available for DISC-mediated activation (By similarity). Inhibits intrinsic apoptotic pathway in response to a wide range of stresses, through its interaction with BAX resulting in BAX inactivation, preventing mitochondrial dysfunction and release of pro-apoptotic factors (PubMed:16505176) (PubMed:24312627). Inhibits calcium-mediated cell death by functioning as a cytosolic calcium buffer, dissociating its interaction with CASP8 and maintaining calcium homeostasis (By similarity). Negatively regulates oxidative stress-induced apoptosis by phosphorylation-dependent suppression of the mitochondria-mediated intrinsic pathway, by blocking CASP2 activation and BAX translocation (By similarity). Negatively regulates hypoxia-induced apoptosis in part by inhibiting the release of cytochrome c from mitochondria in a caspase-independent manner (By similarity). Also inhibits TNF-induced necrosis by preventing TNF-signaling pathway through TNFRSF1A interaction abrogating the recruitment of RIPK1 to complex I (PubMed:24440909). Finally through its role as apoptosis repressor, promotes vascular remodeling through inhibition of apoptosis and stimulation of proliferation, in response to hypoxia (PubMed:22082675). Inhibits too myoblast differentiation through caspase inhibition (By similarity). Oligomerizes (via CARD doamin) (By similarity). Interacts (via CARD domain) with CASP2; inhibits CASP2 activity in a phosphorylation-dependent manner (By similarity). Interacts with CASP8; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium. Interacts with TFPT; translocates NOL3 into the nucleus and negatively regulated TFPT-induced cell death (By similarity). Interacts directly (via CARD domain) with FAS and FADD (via DED domain); inhibits death-inducing signaling complex (DISC) assembly by inhibiting the increase in FAS-FADD binding induced by FAS activation. Interacts (via CARD domain) with BAX (via a C-terminal 33 residues); inhibits BAX activation and translocation and consequently cytochrome c release from mitochondria. Interacts with PPM1G; may dephosphorylate NOL3 (By similarity). Interacts (via CARD domain) with BBC3 (via BH3 domain); preventing the association of BBC3 with BCL2 and resulting in activation of CASP8 (By similarity). Interacts (via CARD domain) with BAD(via BH3 domain); preventing the association of BAD with BCL2 (By similarity). Interacts directly (via CARD domain) with TNFRSF1A; inhibits TNF-signaling pathway. Phosphorylation at Thr-149 results in translocation to mitochondria. Colocalized with mitochondria in response to oxidative stress. CARD is critical for both extrinsic and intrinsic apoptotic pathways (By similarity). CARD domain mediates a protective effect against myocardial ischemia/reperfusion, oxidative stress and TNF-induced necrosis (PubMed:24440909). The C-terminal domain (amino acids 99 to 220) is involved in calcium binding and plays a protective role in calcium-mediated cell death (By similarity). Phosphorylation at Thr-149 is required for its antiapoptotic effect by blocking death-inducing signaling complex death-inducing signaling complex (DISC) activity through the control of interaction with CASP8. Phosphorylation at Thr-149 results in translocation to mitochondria and this translocation enables the binding to CASP8. Dephosphorylated at Thr-149 by calcineurin; doesn't inhibit the association between FADD and CASP8 and the consequent apoptosis. Polyubiquitinated by MDM2; promoting proteasomal-dependent degradation in response to apoptotic stimuli. Mice homozygous for the NOL3-null allele are born normally and externally indistinguishable from littermates of other genotypes. NOL3-null mice grew to adulthood without any abnormalities in their general health and appearance under resting conditions. Under biomechanical stress, NOL3-deficient mice develop accelerated cardiomyopathy which is characterized by reduced contractile function, cardiac enlargement, and myocardial fibrosis. Likewise, under ischemia/reperfusion injury of NOL3-deficient mice have a markedly increased myocardial infarct sizes (PubMed:16505176). Double homozygous knockout mice for NOL3 and SGCD have an enhanced myofiber death and subsequent dystrophic disease (PubMed:24312627).