An increase in mitochondrial TOM activates apoptosis to drive retinal neurodegeneration

Periasamy, A; Mitchell, N; Zaytseva, O; Chahal, AS; Zhao, J; Colman, PM; Quinn, LM; Gulbis, JM

Author(s): Periasamy, A; Mitchell, N; Zaytseva, O; Chahal, AS; Zhao, J; Colman, PM; Quinn, LM; Gulbis, JM;
Details: Publication Year 2022-12-14,Volume 12,Issue #1,Page 21634
Journal Title: Scientific Reports
Abstract: Intronic polymorphic TOMM40 variants increasing TOMM40 mRNA expression are strongly correlated to late onset Alzheimer's Disease. The gene product, hTomm40, encoded in the APOE gene cluster, is a core component of TOM, the translocase that imports nascent proteins across the mitochondrial outer membrane. We used Drosophila melanogaster eyes as an in vivo model to investigate the relationship between elevated Tom40 (the Drosophila homologue of hTomm40) expression and neurodegeneration. Here we provide evidence that an overabundance of Tom40 in mitochondria invokes caspase-dependent cell death in a dose-dependent manner, leading to degeneration of the primarily neuronal eye tissue. Degeneration is contingent on the availability of co-assembling TOM components, indicating that an increase in assembled TOM is the factor that triggers apoptosis and degeneration in a neural setting. Eye death is not contingent on inner membrane translocase components, suggesting it is unlikely to be a direct consequence of impaired import. Another effect of heightened Tom40 expression is upregulation and co-association of a mitochondrial oxidative stress biomarker, DmHsp22, implicated in extension of lifespan, providing new insight into the balance between cell survival and death. Activation of regulated death pathways, culminating in eye degeneration, suggests a possible causal route from TOMM40 polymorphisms to neurodegenerative disease.
Publisher: NPG
Keywords: Animals; Mitochondrial Membrane Transport Proteins/metabolism; Membrane Transport Proteins/metabolism; Drosophila melanogaster/genetics/metabolism; Neurodegenerative Diseases/genetics/metabolism; Mitochondria/genetics/metabolism; Apoptosis/genetics; Carrier Proteins/metabolism; Mitochondrial Proteins/genetics/metabolism; Protein Transport; Saccharomyces cerevisiae Proteins/metabolism
Research Division(s): Structural Biology
PubMed ID: 36517509
Publisher's Version: https://doi.org/10.1038/s41598-022-23280-z
Open Access at Publisher's Site: https://doi.org/10.1038/s41598-022-23280-z
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2022-12-22 08:59:57

Last Modified: 2022-12-22 09:00:14