Complex I Binding by a Virally Encoded RNA Regulates Mitochondria-Induced Cell Death

Abstract

We previously carried out T2D linkage analysis in the families of many of our stage 1 cases (10). None of the 10 loci in Table 1 had large T2D logarithm of the odds (LOD) scores, although those for FTO and TCF7L2 were 0.63 and 0.60 and so were nominally significant. LOD scores for six of the 10 loci were greater than 0.2, as compared to 2.2 that would be expected for random genome locations. This suggests enrichment for T2D-associated loci in regions with modest evidence of T2D linkage (P = 0.01) but that the power of the linkage approach was insufficient to distinguish these signals from background noise.The ability to construct a list of ten robust and replicated T2D-associated loci (Table 1) represents a landmark in efforts to identify genetic variants that predispose to complex human diseases, although the specific predisposing variants and even the relevant genes remain to be defined. We examined the combined risk of T2D based on these 10 loci in our stage 1 + 2 sample by constructing a logistic regression model and predicting T2D risk for each person (8). We found a fourfold variation in T2D risk from the lowest to highest predicted risk groups, which is of potential interest for a personalized preventive-medicine program (Fig. 2). However, these predictions from our data may be biased as compared to predictions based on the general population, likely owing to the overestimation of ORs due to the "winner's curse," enrichment for familial T2D cases, and exclusion of individuals with impaired glucose tolerance or impaired fasting glucose.Thirty years ago, James V. Neel labeled T2D as "the geneticist's nightmare" (32), predicting that the discovery of genetic factors in T2D would be thoroughly challenging. Until recently, his prediction has proven true. Although large samples and collaboration among three groups were required, we can confidently state that new diabetes risk factors have been identified. Each gene discovery points to a pathway that contributes to pathogenesis, and all of these proteins and their relevant pathways represent potential drug targets for the prevention or treatment of diabetes. Based on the number of other interesting results observed in these studies, it is likely that there are additional T2D-predisposing loci to be found. Even though much remains to be done, we are at last awakening from Jim Neel's nightmare.

Increased Resistance of Complex I Mutants to Phytosphingosine-induced Programmed Cell Death

“…Other work has shown that complex I inhibition induces apoptosis in mammalian cells (45,46) and that caspase cleavage of the 75-kDa subunit of complex I was claimed to be required for apoptosis (47). Furthermore, it appears that complex I is also involved in virus-induced apoptosis (48,49) and in the interferon-␤ and retinoic acid-induced cancer cell death (50). Our results are in line with these findings and point to a central role of complex I in mediating programmed cell death in filamentous fungi.…”

Discrete Clusters of Virus-Encoded MicroRNAs Are Associated with Complementary Strands of the Genome and the 7.2-Kilobase Stable Intron in Murine Cytomegalovirus

“…Although extensive work has been undertaken in the characterization of CMV open reading frames which are important for viral function and immune evasion, there is still a lack of understanding in the area of CMV-host interactions, which evades the development of effective therapeutics (9). A recent report with HCMV demonstrated that a 2.7-kb ncRNA interacts with components of the mitochondrial respiratory chain complex and thereby modulates cellular metabolic activity in order to enable a productive viral life cycle (42). Clearly, there are numerous potential mechanisms by which noncoding RNAs, including miRNAs, could influence viral infection and latency.…”

Quantitative Proteomic Analyses of Human Cytomegalovirus-Induced Restructuring of Endoplasmic Reticulum-Mitochondrial Contacts at Late Times of Infection

“…By early times, HCMV infection also encodes an untranslated beta 2.7 RNA that localizes to mitochondria (17,18). Beta 2.7 RNA interacts with the GRIM-19 subunit of mitochondrial complex I and prevents its re-localization from the inner mitochondrial membrane to discrete perinuclear sites (19). Thus, HCMV infection redundantly blocks mitochondrial-mediated proapoptotic signaling pathways.…”