Erk5-induced Klf2 expression follows a biphasic expression profile under flow. At the onset of laminar blood flow, Erk5-induced Klf2 expression occurs in two distinct pathways. The first occurs through MEKK2/3-MEK5-ERK5 complex’s phosphorylation cascade and Erk5 nuclear shuttling (1A), upstream of which is hypothesized to be mechanosensitive. This transient signal reaches an activity maximum following 20 min of LSS and then subsides. Around the same time, LSS induces opening of mechanosensitive calcium channels such as Piezo1 (1B). Mitochondrial calcium uniporters open in this calcium rich environment, causing the organelle to rapidly divide at the expense of increased mitochondrial ROS, resulting in some mitochondria to lose function (2). Through PINK1 signaling, these damaged mitochondria become ubiquitinated, enabling the autophagosome receptor p62 to switch to its active monomer form by binding to its ubiquitinated cargo (3). In this form, p62 enhances Erk5 signaling by binding to both MEKK2/3 and MEK5 through its PB1 domain, providing sustained Erk5-induced Klf2 expression (4). p62 subsequently shuttles its bound mitochondria to autophagosome, producing mitophagic flux under LSS (5).