The mitochondrial proton motive force(pmf)is a critical driver of cellular energy production and influences various cellular processes.Dysregulation of pmf is implicated in a range of diseases,including neurodegenerat...The mitochondrial proton motive force(pmf)is a critical driver of cellular energy production and influences various cellular processes.Dysregulation of pmf is implicated in a range of diseases,including neurodegenerative diseases,mitochondrial diseases,cancer and aging-related pathologies.Currently,an efficient strategy to rescue ATP production and mitigate reactive oxygen species(ROS)generation under conditions of energy deprivation is lacking.Here,we engineered a light-sensitive,mitochondria-targeting proton-pumping rhodopsin(PPR),mt-EcGAPR,capable of generating an efficient pmf for ATP synthesis while simultaneously mitigating reactive oxygen species(ROS)generation during stress and decreasing DNA double-strand breaks(DSBs).Owing to its transparency to visible light,eye is the ideal candidate for the noninvasive application of mt-EcGAPR in the treatment of mitochondria-related retinal degenerative diseases.Using a silicone oil-induced ocular hypertension glaucoma mouse model,we demonstrate that ambient light activation of mt-EcGAPR significantly increased ATP production,suppressed ROS accumulation,and protected retinal ganglion cells(RGCs)from degeneration.Mechanistically,mt-EcGAPR inhibited endoplasmic reticulum(ER)stress-ATF6-gasdermin D(GSDMD)-mediated pyroptosis,thereby preserving retinal structure and function.This intervention ultimately led to improved visual acuity in glaucomatous eyes of mice.Collectively,our findings establish mt-EcGAPR as a promising therapeutic strategy for glaucoma and potentially other neurodegenerative diseases associated with mitochondrial dysfunction and impaired bioenergetics.展开更多
基金supported by the National Natural Science Foundation of China(NSF,Grants#92054103 and#32071137 to J.S.K.,#T2325008,#82588301 and#82021002 to J.Y.Z.,#32000522 to P.P.L.)JSK was also supported by the Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University(Grant#ZYCXTD2023014)+7 种基金Funding was provided by the Ministry of Science and Technology of China(MOST,Grants#2022ZD0208604,#2022ZD0208605,#2024YFC2510800,and#2024ZD0530302 to J.Y.Z.,#2022ZD0210000 to B.Y.)the National Key Research and Development Program of China(Grant#2024YFC2510800)P.P.L.was funded by the Joint Construction Program for Medical Science and Technology Development of Henan Province of China(Grant#2018020088)the Natural Science Foundation of Henan Province of China(Grant#202300410420)Additional support came from the Science and Technology Commission of Shanghai Municipality(Grants#21TQ013 to J.Y.Z.and#25TQ009 to B.Y.)from the Key Research and Development Program of Ningxia(Grant#2022BEG02046 to J.Y.Z.)This work has been supported by the New Cornerstone Science Foundation through the New Cornerstone Investigator Programthe XPLORER PRIZE to J.Y.Z.J.Y.Z.is a SANS explorer scholar.
文摘The mitochondrial proton motive force(pmf)is a critical driver of cellular energy production and influences various cellular processes.Dysregulation of pmf is implicated in a range of diseases,including neurodegenerative diseases,mitochondrial diseases,cancer and aging-related pathologies.Currently,an efficient strategy to rescue ATP production and mitigate reactive oxygen species(ROS)generation under conditions of energy deprivation is lacking.Here,we engineered a light-sensitive,mitochondria-targeting proton-pumping rhodopsin(PPR),mt-EcGAPR,capable of generating an efficient pmf for ATP synthesis while simultaneously mitigating reactive oxygen species(ROS)generation during stress and decreasing DNA double-strand breaks(DSBs).Owing to its transparency to visible light,eye is the ideal candidate for the noninvasive application of mt-EcGAPR in the treatment of mitochondria-related retinal degenerative diseases.Using a silicone oil-induced ocular hypertension glaucoma mouse model,we demonstrate that ambient light activation of mt-EcGAPR significantly increased ATP production,suppressed ROS accumulation,and protected retinal ganglion cells(RGCs)from degeneration.Mechanistically,mt-EcGAPR inhibited endoplasmic reticulum(ER)stress-ATF6-gasdermin D(GSDMD)-mediated pyroptosis,thereby preserving retinal structure and function.This intervention ultimately led to improved visual acuity in glaucomatous eyes of mice.Collectively,our findings establish mt-EcGAPR as a promising therapeutic strategy for glaucoma and potentially other neurodegenerative diseases associated with mitochondrial dysfunction and impaired bioenergetics.
