Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid- beta precursor protein) (PubMed:12522139, PubMed:12679784, PubMed:12740439, PubMed:12763021, PubMed:24941111, PubMed:30598546, PubMed:30630874). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity (PubMed:12522139, PubMed:12679784, PubMed:12740439, PubMed:12763021, PubMed:24941111). Besides its role in gamma-secretase complex, acts as a regulator of AMP-activated protein kinase (AMPK) activity in response to calorie restriction: binds metformin, an antidiabetic drug, promoting association with ATP6AP1, a subunit of the V-ATPase complex, leading to V-ATPase complex inhibition on lysosomes and AMPK activation via the AXIN1-STK11/LKB1 axis (By similarity). {ECO:0000250|UniProtKB:Q9CQR7, ECO:0000269|PubMed:12522139, ECO:0000269|PubMed:12679784, ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:12763021, ECO:0000269|PubMed:24941111, ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, ECO:0000305}. This is the function of PSENEN (presenilin enhancer, gamma-secretase subunit, ENSG00000205155).