Although mitochondrial dysfunction is a consistent feature of Alzheimer's disease in the brain and blood, the molecular mechanisms behind these phenomena are unknown. Here we have replicated our previous findings demonstrating reduced expression of nuclear-encoded oxidative phosphorylation (OXPHOS) subunits and subunits required for the translation of mitochondrial-encoded OXPHOS genes in blood from people with Alzheimer's disease and mild cognitive impairment. Interestingly this was accompanied by increased expression of some mitochondrial-encoded OXPHOS genes, namely those residing closest to the transcription start site of the polycistronic heavy chain mitochondrial transcript (MT-ND1, MT-ND2, MT-ATP6, MT-CO1, MT-CO2, MT-C03) and MT-ND6 transcribed from the light chain. Further we show that mitochondrial DNA copy number was unchanged suggesting no change in steady-state numbers of mitochondria. We suggest that an imbalance in nuclear and mitochondrial genome-encoded OXPHOS transcripts may drive a negative feedback loop reducing mitochondrial translation and compromising OXPHOS efficiency, which is likely to generate damaging reactive oxygen species.

Birdshot Uveitis (Birdshot) is a rare eye condition that affects HLA-A29-positive individuals and could be considered a prototypic member of the recently proposed ‘MHC-I (major histocompatibility complex class I)-opathy’ family. Genetic studies have pinpointed the endoplasmic reticulum aminopeptidase (ERAP1) and (ERAP2) genes as shared associations across MHC-I-opathies, which suggests ERAP dysfunction may be a root cause for MHC-I-opathies. We mapped the ERAP1 and ERAP2 haplotypes in 84 Dutch cases and 890 controls. We identified association at variant rs10044354, which mediated a marked increase in ERAP2 expression. We also identified and cloned an independently associated ERAP1 haplotype (tagged by rs2287987) present in more than half of the cases; this ERAP1 haplotype is also the primary risk and protective haplotype for other MHC-I-opathies. We show that the risk ERAP1 haplotype conferred significantly altered expression of ERAP1 isoforms in transcriptomic data (n = 360), resulting in lowered protein expression and distinct enzymatic activity. Both the association for rs10044354 (meta-analysis: odds ratio (OR) [95% CI]=2.07[1.58–2.71], P = 1.24 × 10(−7)) and rs2287987 (OR[95% CI]: =2.01[1.51–2.67], P = 1.41 × 10(−6)) replicated and showed consistent direction of effect in an independent Spanish cohort of 46 cases and 2103 controls. In both cohorts, the combined rs2287987-rs10044354 haplotype associated with Birdshot more strongly than either variant alone [meta-analysis: P=3.9 × 10(−9)]. Finally, we observed that ERAP2 protein expression is dependent on the ERAP1 background across three European populations (n = 3353). In conclusion, a functionally distinct combination of ERAP1 and ERAP2 are a hallmark of Birdshot and provide rationale for strategies designed to correct ERAP function for treatment of Birdshot and MHC-I-opathies more broadly.

Considerable evidence suggests that mitochondrial dysfunction occurs early in Alzheimer's disease, both in affected brain regions and in leukocytes, potentially precipitating neurodegeneration through increased oxidative stress. Epigenetic processes are emerging as a dynamic mechanism through which environmental signals may contribute to cellular changes, leading to neuropathology and disease. Until recently, little attention was given to the mitochondrial epigenome itself, as preliminary studies indicated an absence of DNA modifications. However, recent research has demonstrated that epigenetic changes to the mitochondrial genome do occur, potentially playing an important role in several disorders characterized by mitochondrial dysfunction. This review explores the potential role of mitochondrial epigenetic dysfunction in Alzheimer's disease etiology and discusses some technical issues pertinent to the study of these processes.

DNA methylation is an important epigenetic mechanism involved in gene regulation, with alterations in DNA methylation in the nuclear genome being linked to numerous complex diseases. Mitochondrial DNA methylation is a phenomenon that is receiving ever-increasing interest, particularly in diseases characterized by mitochondrial dysfunction; however, most studies have been limited to the investigation of specific target regions. Analyses spanning the entire mitochondrial genome have been limited, potentially due to the amount of input DNA required. Further, mitochondrial genetic studies have been previously confounded by nuclear-mitochondrial pseudogenes. Methylated DNA Immunoprecipitation Sequencing is a technique widely used to profile DNA methylation across the nuclear genome; however, reads mapped to mitochondrial DNA are often discarded. Here, we have developed an approach to control for nuclear-mitochondrial pseudogenes within Methylated DNA Immunoprecipitation Sequencing data. We highlight the utility of this approach in identifying differences in mitochondrial DNA methylation across regions of the human brain and pre-mortem blood. We were able to correlate mitochondrial DNA methylation patterns between the cortex, cerebellum and blood. We identified 74 nominally significant differentially methylated regions (p < 0.05) in the mitochondrial genome, between anatomically separate cortical regions and the cerebellum in matched samples (N = 3 matched donors). Further analysis identified eight significant differentially methylated regions between the total cortex and cerebellum after correcting for multiple testing. Using unsupervised hierarchical clustering analysis of the mitochondrial DNA methylome, we were able to identify tissue-specific patterns of mitochondrial DNA methylation between blood, cerebellum and cortex. Our study represents a comprehensive analysis of the mitochondrial methylome using pre-existing Methylated DNA Immunoprecipitation Sequencing data to identify brain region-specific patterns of mitochondrial DNA methylation.

There are well-documented racial differences in age-of-onset and laterality of colorectal cancer. Epigenetic age acceleration is postulated to be an underlying factor. However, comparative studies of side-specific colonic tissue epigenetic aging are lacking. Here, we performed DNA methylation analysis of matched right and left biopsies of normal colon from 128 individuals. Among African Americans (n = 88), the right colon showed accelerated epigenetic aging as compared with individual-matched left colon (1.51 years; 95% confidence interval [CI] = 0.62 to 2.40 years; 2-sided P = .001). In contrast, among European Americans (n = 40), the right colon shows remarkable age deceleration (1.93 years; 95% CI = 0.65 to 3.21 years; 2-sided P = .004). Further, epigenome-wide analysis of DNA methylation identifies a unique pattern of hypermethylation in African American right colon. Our study is the first to report such race and side-specific differences in epigenetic aging of normal colon, providing novel insight into the observed younger age-of-onset and relative preponderance of right-side colon neoplasia in African Americans.