Mitochondrial Genetics Reinforces Multiple Layers of Interaction in Alzheimer’s Disease

Abstract

Nuclear DNA has been the main source of genome-wide loci association in neurodegenerative diseases, only partially accounting for the heritability of Alzheimer’s Disease (AD). In this context, mitochondrial DNA (mtDNA) is gaining more attention. Here, we investigated mitochondrial genes and genetic variants that may influence mild cognitive impairment and AD, through an integrative analysis including differential gene expression and mitochondrial genome-wide epistasis. We assessed the expression of mitochondrial genes in different brain tissues from two public RNA-Seq databases (GEO and GTEx). Then, we analyzed mtDNA from the ADNI Cohort and investigated epistasis regarding mitochondrial variants and levels of Aβ1−42, TAU, and Phosphorylated TAU (PTAU) from cognitively healthy controls, and both mild cognitive impairment (MCI) and AD cases. We identified multiple differentially expressed mitochondrial genes in the comparisons between cognitively healthy individuals and AD patients. We also found increased protein levels in MCI and AD patients when compared to healthy controls, as well as novel candidate networks of mtDNA epistasis, which included variants in all mitochondrially-encoded oxidative phosphorylation complexes, 12S rRNA and MT-DLOOP. Our results highlight layers of potential interactions involving mitochondrial genetics and suggest specific molecular alterations as potential biomarkers for AD.

A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in the human and mouse brains

“…Out of these gene markers, mt-Rnr2 is involved in synthesizing neuroprotective factors against neurodegeneration by suppressing apoptotic cell death (Hashimoto et al, 2001). Other markers ( e,g., mt-Rnr1 and mt-Nd5 ) are associated with the phosphorylated Tau protein levels in cerebrospinal fluid (Cavalcante et al, 2022). While this subtype was rarely detected in our single-cell ATAC data, we were able to map the cell subtype to the area around the subventricular zone by the expression of its cell-type-specific markers in the spatial transcriptomics data ( Figure 6D and 6E, top ).…”

Targeted Mitochondrial Epigenetics: A New Direction in Alzheimer’s Disease Treatment

“…In general, DNA hypermethylation inhibits gene expression, whereas DNA demethylation induces gene reactivation and expression [ 68 , 69 ]. Based on the available results, we believe that in AD, mtDNA hypermethylation causes damage to mitochondrial biogenesis and the normal functioning of the mitochondrial respiratory chain, and that the demethylation of the D-loop region is likely a compensatory mechanism for this damage [ 70 , 71 ]. Interestingly, AD specimens from different analytical tissues or different stages of the disease may show different results.…”

Mitochondrial Ca2+ Signaling and Bioenergetics in Alzheimer’s Disease

“…The involvement of these cell types in AD pathogenesis has also been confirmed by genome-wide association studies (GWAS). These studies describe SAD-associated genetic polymorphisms in genes involved in microglia, astrocytes and neuronal functions [ 21 , 22 , 23 , 24 ], as well as genes encoding mitochondria complexes or proteins involved in energy metabolism [ 25 , 26 , 27 , 28 ].…”