ZFIN ID: ZDB-PUB-200403-96
Chemoptogenetic ablation of neuronal mitochondria in vivo with spatiotemporal precision and controllable severity
Xie, W., Jiao, B., Bai, Q., Ilin, V.A., Sun, M., Burton, C.E., Kolodieznyi, D., Calderon, M.J., Stolz, D.B., Opresko, P.L., St Croix, C.M., Watkins, S., Van Houten, B., Bruchez, M.P., Burton, E.A.
Date: 2020
Source: eLIFE   9: (Journal)
Registered Authors: Burton, Edward A.
Keywords: biochemistry, cell death, chemical biology, chemoptogenetics, mitochondria, motor function, neuroscience, respiration, zebrafish
MeSH Terms:
  • Adenosine Triphosphate/metabolism
  • Animals
  • Animals, Genetically Modified
  • Behavior, Animal
  • Electrophysiology
  • Embryo, Nonmammalian
  • Fluorescent Dyes
  • Gene Expression Regulation/drug effects
  • Gene Expression Regulation/radiation effects
  • Light
  • Mitochondria
  • Motor Activity
  • Neurons
  • Optogenetics/instrumentation*
  • Optogenetics/methods*
  • Oxygen Consumption
  • Single-Cell Analysis
  • Spatio-Temporal Analysis
  • Zebrafish
PubMed: 32180546 Full text @ Elife
Mitochondrial dysfunction is implicated in the pathogenesis of multiple neurological diseases, but elucidation of underlying mechanisms is limited experimentally by the inability to damage specific mitochondria in defined neuronal groups. We developed a precision chemoptogenetic approach to target neuronal mitochondria in the intact nervous system in vivo. MG2I, a chemical fluorogen, produces singlet oxygen when bound to the fluorogen-activating protein dL5** and exposed to far-red light. Transgenic zebrafish expressing dL5** within neuronal mitochondria showed dramatic MG2I- and light-dependent neurobehavioral deficits, caused by neuronal bioenergetic crisis and acute neuronal depolarization. These abnormalities resulted from loss of neuronal respiration, associated with mitochondrial fragmentation, swelling and elimination of cristae. Remaining cellular ultrastructure was preserved initially, but cellular pathology downstream of mitochondrial damage eventually culminated in neuronal death. Our work provides powerful new chemoptogenetic tools for investigating mitochondrial homeostasis and pathophysiology and shows a direct relationship between mitochondrial function, neuronal biogenetics and whole-animal behavior.