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Peer-reviewedCC BY-NC-SA 4.0Molecular Biology of the Cell

Distinct mitochondrial states modulate α-synuclein toxicity

  • Ishita Haider1
  • Annabel Vivian P. Almazan1
  • Breonna Gillespie1
  • Sonu Yadav1
  • Rajalakshmi Santhanakrishnan1
  • Roselle Bea P. Almazan1
  • Kamalika Biswas1
  • Christina Minassian1
  • Shulin Ju1
  • Quan Zhong
  1. 1Department of Biological Sciences, Wright State University, Dayton, 45435 OH
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Abstract

Abnormal α-synuclein (α-syn) accumulation and mitochondrial dysfunction are central features of Parkinson's disease (PD), and increasing evidence suggests that these processes are closely connected. Using yeast models to manipulate mitochondrial metabolic states, we investigated how mitochondrial activity may affect α-syn accumulation and toxicity. Under the fermentative growth condition, we found that α-syn localized predominantly to the plasma membrane and was non-toxic. Respiratory growth induced cytoplasmic α-syn accumulation, mitochondrial abnormalities, and marked toxicity dependent on α-syn expression and membrane binding. Surprisingly, genetic disruption of mitochondrial respiration also enhanced α-syn toxicity despite causing little α-syn accumulation, indicating that both increased demand of mitochondrial respiratory function and compromised respiratory capacity can sensitize cells to α-syn toxicity. Overexpression of HAP4, a master regulator of mitochondrial biogenesis and respiratory gene expression, suppressed α-syn toxicity, but this protection required functional mitochondria. Together, these findings demonstrate that distinct mitochondrial functional states exert markedly different effects on α-syn toxicity and reveal a complex relationship between mitochondrial function and cellular response to α-syn expression. These models provide a new system for investigating how changes in mitochondrial function contribute to α-syn-induced cellular stress.

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Cite

BibTeXRIS
BibTeX
@article{haider2026distinct,
  title = {{Distinct mitochondrial states modulate α-synuclein toxicity}},
  author = {Ishita Haider and Annabel Vivian P. Almazan and Breonna Gillespie and Sonu Yadav and Rajalakshmi Santhanakrishnan and Roselle Bea P. Almazan and Kamalika Biswas and Christina Minassian and Shulin Ju and Quan Zhong},
  journal = {Molecular Biology of the Cell},
  year = {2026},
  month = oct,
  doi = {10.1091/mbc.e25-11-0541},
  url = {https://doi.org/10.1091/mbc.e25-11-0541},
  note = {CC BY-NC-SA 4.0},
}
RIS
TY  - JOUR
TI  - Distinct mitochondrial states modulate α-synuclein toxicity
AU  - Ishita Haider
AU  - Annabel Vivian P. Almazan
AU  - Breonna Gillespie
AU  - Sonu Yadav
AU  - Rajalakshmi Santhanakrishnan
AU  - Roselle Bea P. Almazan
AU  - Kamalika Biswas
AU  - Christina Minassian
AU  - Shulin Ju
AU  - Quan Zhong
PY  - 2026
DA  - 2026/10/26
JO  - Molecular Biology of the Cell
DO  - 10.1091/mbc.e25-11-0541
UR  - https://doi.org/10.1091/mbc.e25-11-0541
AB  - Abnormal α-synuclein (α-syn) accumulation and mitochondrial dysfunction are central features of Parkinson's disease (PD), and increasing evidence suggests that these processes are closely connected. Using yeast models to manipulate mitochondrial metabolic states, we investigated how mitochondrial activity may affect α-syn accumulation and toxicity. Under the fermentative growth condition, we found that α-syn localized predominantly to the plasma membrane and was non-toxic. Respiratory growth induced cytoplasmic α-syn accumulation, mitochondrial abnormalities, and marked toxicity dependent on α-syn expression and membrane binding. Surprisingly, genetic disruption of mitochondrial respiration also enhanced α-syn toxicity despite causing little α-syn accumulation, indicating that both increased demand of mitochondrial respiratory function and compromised respiratory capacity can sensitize cells to α-syn toxicity. Overexpression of HAP4, a master regulator of mitochondrial biogenesis and respiratory gene expression, suppressed α-syn toxicity, but this protection required functional mitochondria. Together, these findings demonstrate that distinct mitochondrial functional states exert markedly different effects on α-syn toxicity and reveal a complex relationship between mitochondrial function and cellular response to α-syn expression. These models provide a new system for investigating how changes in mitochondrial function contribute to α-syn-induced cellular stress.
SN  - 1059-1524
SN  - 1939-4586
ER  -