Bioenergetic adaptation in response to autophagy regulators during rotenone exposure

Samantha Giordano, Matthew Dodson, Saranya Ravi, Matthew Redmann, Xiaosen Ouyang, Victor M.Darley Usmar, Jianhua Zhang

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Parkinson's disease is the second most common neurodegenerative disorder with both mitochondrial dysfunction and insufficient autophagy playing a key role in its pathogenesis. Among the risk factors, exposure to the environmental neurotoxin rotenone increases the probability of developing Parkinson's disease. We previously reported that in differentiated SH-SY5Y cells, rotenone-induced cell death is directly related to inhibition of mitochondrial function. How rotenone at nM concentrations inhibits mitochondrial function, and whether it can engage the autophagy pathway necessary to remove damaged proteins and organelles, is unknown. We tested the hypothesis that autophagy plays a protective role against rotenone toxicity in primary neurons. We found that rotenone (10-100 nM) immediately inhibited cellular bioenergetics. Concentrations that decreased mitochondrial function at 2 h, caused cell death at 24 h with an LD50 of 10 nM. Overall, autophagic flux was decreased by 10 nM rotenone at both 2 and 24 h, but surprisingly mitophagy, or autophagy of the mitochondria, was increased at 24 h, suggesting that a mitochondrial-specific lysosomal degradation pathway may be activated. Up-regulation of autophagy by rapamycin protected against cell death while inhibition of autophagy by 3-methyladenine exacerbated cell death. Interestingly, while 3-methyladenine exacerbated the rotenone-dependent effects on bioenergetics, rapamycin did not prevent rotenone-induced mitochondrial dysfunction, but caused reprogramming of mitochondrial substrate usage associated with both complex I and complex II activities. Taken together, these data demonstrate that autophagy can play a protective role in primary neuron survival in response to rotenone; moreover, surviving neurons exhibit bioenergetic adaptations to this metabolic stressor.

Original languageEnglish (US)
Pages (from-to)625-633
Number of pages9
JournalJournal of neurochemistry
Issue number5
StatePublished - Dec 2014
Externally publishedYes


  • 3-methyladenine
  • Autophagy
  • Mitochondria
  • Primary neuron
  • Rapamycin
  • Rotenone

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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