Extracellular matrix stiffness regulates mitochondrial dynamics through PINCH-1- and kindlin-2-mediated signalling

Abstract

Proper control of mitochondrial morphology is crucial for many vital cellular processes including energy production, cell cycle and apoptosis. We show here that extracellular matrix (ECM) stiffness regulates mitochondrial morphology through integrin-dependent signaling pathways. ECM stiffening promotes mitochondrial fusion and concomitantly suppressed DRP1 expression and mitochondrial fission. Depletion of kindlin-2, an integrin-binding protein, inhibits ECM stiffening-induced mitochondrial fusion but fails to release ECM stiffening-induced suppression of DRP1 expression and mitochondrial fission. On the other hand, depletion of PINCH-1, a focal adhesion protein whose level is increased in response to ECM stiffening, does not significantly affect mitochondrial fusion but abolishes ECM stiffening-induced suppression of DRP1 expression and mitochondrial fission. Finally, overexpression of PINCH-1 is sufficient to override ECM softening-induced up-regulation of DRP1 expression and mitochondrial fission. Our results demonstrate a crucial role of ECM mechanics in regulation of mitochondrial dynamics and suggest that this regulation is mediated through two distinct signaling mechanisms, namely kindlin-2-dependent up-regulation of mitochondrial fusion and PINCH-1-dependent suppression of DRP1 expression and mitochondrial fission. • Mitochondrial morphology is influenced by extracellular matrix (ECM) stiffness. • ECM stiffening promotes mitochondrial fusion and suppresses mitochondrial fission. • Kindlin-2 mediates ECM stiffening-induced promotion of mitochondrial fusion. • PINCH-1 mediates ECM stiffening-induced suppression of mitochondrial fission. • PINCH-1 suppresses mitochondrial fission through inhibition of DRP1 expression.