Abstract
Communication between intracellular organelles including lysosomes and mitochondria has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other [lysosomal–mitochondrial interaction (LMI)] is emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas [including squamous cell carcinoma of the head and neck (SCCHN)] overexpress transmembrane member 16A (TMEM16A), a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. We have recently shown that TMEM16A drives lysosomal biogenesis; however, its impact on mitochondrial function has not been explored. In this study, we show that in the context of high-TMEM16A SCCHN, (i) patients display increased mitochondrial content, specifically complex I; (ii) in vitro and in vivo models uniquely depend on mitochondrial complex I activity for growth and survival; (iii) NRF2 signaling is a critical linchpin that drives mitochondrial function, and (iv) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that coordinated lysosomal and mitochondrial activity and biogenesis via LMI drive tumor proliferation and facilitate a functional interaction between lysosomal and mitochondrial networks. Therefore, inhibition of LMI instauration may serve as a therapeutic strategy for patients with SCCHN.
Implications: Intervention of LMI may serve as a therapeutic approach for patients with high TMEM16A–expressing SCCHN.