Aging-associated H3K9 trimethylation reduces the mitochondrial unfolded protein response capacity leading to neurodegeneration and functional impairment of the olfactory system

Abstract

Aging is one of the main risk factors for the onset and severity of neurodegenerative diseases. Progressive accumulation of dysfunctional mitochondria is particularly harmful in post-mitotic cells such as neurons, contributing to aging phenotypes including neurodegeneration. The mitochondrial unfolded protein response (UPRMT) is a stress-triggered cellular mechanism to cope with mitochondrial dysfunction and is associated with the transcriptional activation of speficic mitochondrial chaperones, proteases and antioxidant enzymes. The activation of the UPRMT requires an open chromatin state characterized by the dimethylation of H3K9. In contrast, age-associated trimethylated H3K9 generates a closed chromatin state that impairs the transcriptional activation of the UPRMT. Whether the decline in the adaptive capacity of the UPRMT caused by age-associated H3K9 trimethylation contributes to neurodegeneration and impairment of nervous system function has just begun to be elucidated. Here, using Drosophila melanogaster, we demonstrate that the age-associated functional decline of olfactory function is associated with an increase in H3K9 trimethylation and a decrease in UPRMT activation in olfactory neurons, leading to mitochondrial dysfunction and neurodegeneration. Remarkably, reducing H3K9Me3 levels by knockdown of the methyltransferase dSetdb1 in olfactory neurons of aged organisms enhances the response capacity of the UPRMT, ameliorating age-associated neurodegeneration and mitochondrial abnormalities, and rescuing the decrease in olfactory function. In addition, downregulation of the UPRMT transcriptional modulators in young flies mirrored the impaired functional phenotype observed in aged animals. This data demonstrates that the UPRMT acts as a hormetic surveillance pathway regulating mitochondrial homeostasis and function in olfactory projection neurons. Significantly, this stress-response pathway is epigenetically regulated and contributes to the age-associated loss of neuronal function.

Aging is one of the main risk factors for the onset and severity of neurodegenerative diseases. Progressive accumulation of dysfunctional mitochondria is particularly harmful in post-mitotic cells such as neurons, contributing to aging phenotypes including neurodegeneration. The mitochondrial unfolded protein response (UPRMT) is a stress-triggered cellular mechanism to cope with mitochondrial dysfunction and is associated with the transcriptional activation of speficic mitochondrial chaperones, proteases and antioxidant enzymes. The activation of the UPRMT requires an open chromatin state characterized by the dimethylation of H3K9. In contrast, age-associated trimethylated H3K9 generates a closed chromatin state that impairs the transcriptional activation of the UPRMT. Whether the decline in the adaptive capacity of the UPRMT caused by age-associated H3K9 trimethylation contributes to neurodegeneration and impairment of nervous system function has just begun to be elucidated. Here, using Drosophila melanogaster, we demonstrate that the age-associated functional decline of olfactory function is associated with an increase in H3K9 trimethylation and a decrease in UPRMT activation in olfactory neurons, leading to mitochondrial dysfunction and neurodegeneration. Remarkably, reducing H3K9Me3 levels by knockdown of the methyltransferase dSetdb1 in olfactory neurons of aged organisms enhances the response capacity of the UPRMT, ameliorating age-associated neurodegeneration and mitochondrial abnormalities, and rescuing the decrease in olfactory function. In addition, downregulation of the UPRMT transcriptional modulators in young flies mirrored the impaired functional phenotype observed in aged animals. This data demonstrates that the UPRMT acts as a hormetic surveillance pathway regulating mitochondrial homeostasis and function in olfactory projection neurons. Significantly, this stress-response pathway is epigenetically regulated and contributes to the age-associated loss of neuronal function.