Mitochondrial protein import stress in Parkinson’s disease: the TOM/TIM–PINK1/Parkin–DELE1/HRI axis linking mitochondrial proteostasis to neuronal death

Mitochondrial dysfunction is a hallmark of Parkinson’s disease (PD), but how impaired mitochondrial homeostasis drives the selective death of dopaminergic neurons is still poorly understood. At the center of this problem lies the mitochondrial protein import machinery—the TOM and TIM23 translocases—which doubles as a stress-sensing hub that coordinates two distinct quality control pathways. When import is compromised, the kinase PINK1 accumulates on the mitochondrial surface, recruits Parkin to ubiquitinate outer membrane proteins, and triggers mitophagy. Meanwhile, the stress sensor DELE1 is cleaved and released to the cytosol, where it activates the HRI kinase to phosphorylate eIF2α and engage the integrated stress response (ISR). These two pathways are not independent. Recent work shows they engage in antagonistic crosstalk: the DELE1–HRI–ISR axis suppresses PINK1/Parkin-dependent mitophagy by preserving mitochondrial import efficiency, acting as a molecular brake on organelle clearance. The balance between these pathways is governed by the SIFI E3 ubiquitin ligase complex, which targets both DELE1 and HRI for degradation. Disruption of SIFI causes progressive neurodegeneration in humans. Here we synthesize the structural, biochemical, and genetic evidence that defines the TOM/TIM–PINK1/Parkin–DELE1/HRI signaling axis, examine how its dysregulation contributes to dopaminergic neuron vulnerability, and evaluate therapeutic strategies targeting mitochondrial import stress in PD.