Curbing mitochondrial dysfunction in neurodegeneration: lessons from neurogenetics

講演要旨

Parkinson’s disease (PD) is a common neurodegenerative disorder. Although genes such as PINK1 and Parkin had been linked to familial PD, the pathways they control were unknown.

Dr. Narendra discovered that these genes define a mitochondrial quality control system that detects and eliminates damaged mitochondria. He showed that PINK1 is selectively stabilized on injured mitochondria as a damage sensor and activates Parkin. Activated Parkin is then selectively recruited to these mitochondria, where it marks them with ubiquitin, triggering their removal through mitophagy. He further demonstrated this pathway in vivo, establishing a fundamental mechanism linking mitochondrial damage to neurodegeneration.

As a physician–scientist, Dr. Narendra has extended these discoveries by studying patients with rare neurogenetic disorders to uncover how distinct forms of mitochondrial injury converge on shared mitochondrial damage-sensing mechanisms that govern their resolution. These studies, involving genetic forms of mitochondrial myopathies and ALS, show that diverse disorders engage common damage-sensing and stress response pathways. These pathways both eliminate damaged mitochondria and activate mitochondrial stress signaling through the OMA1–DELE1 axis, preserving cellular function under stress. They further link these pathways to clinical phenotypes and biochemical signatures, informing disease classification, biomarker development, and emerging precision therapeutic strategies.

Together, this work defines a unifying framework for mitochondrial damage responses in neurological disease and has catalyzed therapeutic strategies aimed at restoring mitochondrial quality control, with approaches now advancing toward clinical application.