TY - JOUR
T1 - Nuclear respiratory factor-1 (NRF1) induction drives mitochondrial biogenesis and attenuates amyloid beta-induced mitochondrial dysfunction and neurotoxicity
AU - Massaro, Matteo
AU - Baudo, Gherardo
AU - Lee, Hyunho
AU - Liu, Haoran
AU - Blanco, Elvin
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2025
Y1 - 2025
N2 - Mitochondrial dysfunction is an important driver of neurodegeneration and synaptic abnormalities in Alzheimer's disease (AD). Amyloid beta (Aβ) in mitochondria leads to increased reactive oxygen species (ROS) production, resulting in a vicious cycle of oxidative stress in coordination with a defective electron transport chain (ETC), decreasing ATP production. AD neurons exhibit impaired mitochondrial dynamics, evidenced by fusion and fission imbalances, increased fragmentation, and deficient mitochondrial biogenesis, contributing to fewer mitochondria in brains of AD patients. Nuclear respiratory factor-1 (NRF1) is a regulator of mitochondrial biogenesis through its activation of mitochondrial transcription factor A (TFAM). Our hypothesis posited that NRF1 induction in neuronal cells exposed to amyloid β1-42 (Aβ1-42) would increase de novo mitochondrial synthesis and improve mitochondrial function, restoring neuronal survival. Following NRF1 messenger RNA (mRNA) transfection of Aβ1-42-treated SH-SY5Y cells, a marked increase in mitochondrial mass was observed. Metabolic programming toward enhanced oxidative phosphorylation resulted in increased ATP production. Oxidative stress in the form of mitochondrial ROS accumulation was reduced and mitochondrial membrane potential preserved. Mitochondrial homeostasis was maintained, evidenced by balanced fusion and fission processes. Ultimately, improvement of mitochondrial function was associated with significant decreases in Aβ1-42-induced neuronal death and neurite disruption. Our findings highlight the potential of NRF1 upregulation to counteract Aβ1-42-associated mitochondrial dysfunction and neurodegenerative cell processes, opening avenues for innovative therapeutic approaches aimed at safeguarding mitochondrial health in AD neurons.
AB - Mitochondrial dysfunction is an important driver of neurodegeneration and synaptic abnormalities in Alzheimer's disease (AD). Amyloid beta (Aβ) in mitochondria leads to increased reactive oxygen species (ROS) production, resulting in a vicious cycle of oxidative stress in coordination with a defective electron transport chain (ETC), decreasing ATP production. AD neurons exhibit impaired mitochondrial dynamics, evidenced by fusion and fission imbalances, increased fragmentation, and deficient mitochondrial biogenesis, contributing to fewer mitochondria in brains of AD patients. Nuclear respiratory factor-1 (NRF1) is a regulator of mitochondrial biogenesis through its activation of mitochondrial transcription factor A (TFAM). Our hypothesis posited that NRF1 induction in neuronal cells exposed to amyloid β1-42 (Aβ1-42) would increase de novo mitochondrial synthesis and improve mitochondrial function, restoring neuronal survival. Following NRF1 messenger RNA (mRNA) transfection of Aβ1-42-treated SH-SY5Y cells, a marked increase in mitochondrial mass was observed. Metabolic programming toward enhanced oxidative phosphorylation resulted in increased ATP production. Oxidative stress in the form of mitochondrial ROS accumulation was reduced and mitochondrial membrane potential preserved. Mitochondrial homeostasis was maintained, evidenced by balanced fusion and fission processes. Ultimately, improvement of mitochondrial function was associated with significant decreases in Aβ1-42-induced neuronal death and neurite disruption. Our findings highlight the potential of NRF1 upregulation to counteract Aβ1-42-associated mitochondrial dysfunction and neurodegenerative cell processes, opening avenues for innovative therapeutic approaches aimed at safeguarding mitochondrial health in AD neurons.
KW - Alzheimer's disease
KW - Amyloid beta
KW - Mitochondrial biogenesis
KW - Mitochondrial dysfunction
KW - Nuclear respiratory factor-1 (NRF1)
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U2 - 10.1016/j.neurot.2024.e00513
DO - 10.1016/j.neurot.2024.e00513
M3 - Article
AN - SCOPUS:85213572074
SN - 1933-7213
JO - Neurotherapeutics
JF - Neurotherapeutics
M1 - e00513
ER -