Long noncoding RNAs are generated from the mitochondrial genome and regulated by nuclear-encoded proteins

Human mitochondrial long noncoding RNAs (lncRNAs) have not been described to date. By analysis of deep-sequencing data we have identified three lncRNAs generated from the mitochondrial genome and confirmed their expression by Northern blotting and strand-specific qRT-PCR. We show that the abundance of these lncRNAs is comparable to their complementary mRNAs and that nuclear-encoded mitochondrial proteins involved in RNA processing regulate their expression. We also identify the 5′ and 3′ transcript ends of the three lncRNAs and show that mitochondrial RNase P protein 1 (MRPP1) is important for the processing of these transcripts. Finally, we show that mitochondrial lncRNAs form intermolecular duplexes and that their abundance is cell- and tissue-specific, suggesting a functional role in the regulation of mitochondrial gene expression. Published by Cold Spring Harbor Laboratory Press

The Human Mitochondrial Transcriptome

SummaryThe human mitochondrial genome comprises a distinct genetic system transcribed as precursor polycistronic transcripts that are subsequently cleaved to generate individual mRNAs, tRNAs, and rRNAs. Here, we provide a comprehensive analysis of the human mitochondrial transcriptome across multiple cell lines and tissues. Using directional deep sequencing and parallel analysis of RNA ends, we demonstrate wide variation in mitochondrial transcript abundance and precisely resolve transcript processing and maturation events. We identify previously undescribed transcripts, including small RNAs, and observe the enrichment of several nuclear RNAs in mitochondria. Using high-throughput in vivo DNaseI footprinting, we establish the global profile of DNA-binding protein occupancy across the mitochondrial genome at single-nucleotide resolution, revealing regulatory features at mitochondrial transcription initiation sites and functional insights into disease-associated variants. This integrated analysis of the mitochondrial transcriptome reveals unexpected complexity in the regulation, expression, and processing of mitochondrial RNA and provides a resource for future studies of mitochondrial function (accessed at http://mitochondria.matticklab.com)

Pentatricopeptide repeat domain protein 3 associates with the mitochondrial small ribosomal subunit and regulates translation

AbstractThe basic components and mechanisms of mitochondrial transcription in mammals have been described, however, the components involved in mRNA processing, translation and stability remain largely unknown. In plants, pentatricopeptide domain RNA-binding proteins regulate the stability, expression and translation of mitochondrial transcripts. Here, we investigated the role of an uncharacterized mammalian pentatricopeptide domain protein, pentatricopeptide repeat domain protein 3 (PTCD3), and showed that it is a mitochondrial protein that associates with the small subunit of mitochondrial ribosomes. PTCD3 knockdown and over expression did not affect mitochondrial mRNA levels, suggesting that PTCD3 is not involved in RNA processing and stability. However, lowering PTCD3 in 143B osteosarcoma cells decreased mitochondrial protein synthesis, mitochondrial respiration and the activity of Complexes III and IV, suggesting that PTCD3 has a role in mitochondrial translation.Structured summaryMINT-7033995: PTCD3 (uniprotkb:Q96EY7) associates (MI:0914) with MRPS15 (uniprotkb:P82914) by tandem affinity purification (MI:0676

Compact groups with a dense free abelian subgroup

The compact groups having a dense infinite cyclic subgroup (known as monothetic compact groups) have been studied by many authors for their relevance and nice applications. In this paper we describe in full details the compact groups $K$ with a dense free abelian subgroup $F$ and we describe the minimum rank $r_t(K)$ of such a subgroup $F$ of $K$. Surprisingly, it is either finite or coincides with the density character $d(K)$ of $K$.

Age-related proteostasis and metabolic alterations in Caspase-2-deficient mice

Ageing is a complex biological process for which underlying biochemical changes are still largely unknown. We performed comparative profiling of the cellular proteome and metabolome to understand the molecular basis of ageing in Caspase-2-deficient (Casp2−/−) mice that are a model of premature ageing in the absence of overt disease. Age-related changes were determined in the liver and serum of young (6–9 week) and aged (18–24 month) wild-type and Casp2−/− mice. We identified perturbed metabolic pathways, decreased levels of ribosomal and respiratory complex proteins and altered mitochondrial function that contribute to premature ageing in the Casp2−/− mice. We show that the metabolic profile changes in the young Casp2−/− mice resemble those found in aged wild-type mice. Intriguingly, aged Casp2−/− mice were found to have reduced blood glucose and improved glucose tolerance. These results demonstrate an important role for caspase-2 in regulating proteome and metabolome remodelling during ageing.CH Wilson, S Shalini, A Filipovska, TR Richman, S Davies, SD Martin, SL McGee, J Puccini, A Nikolic, L Dorstyn, and S Kuma

Bench-to-bedside review : targeting antioxidants to mitochondria in sepsis

Peer reviewedPublisher PD

Rescue of skeletal muscle α-actin–null mice by cardiac (fetal) α-actin

Skeletal muscle α-actin (ACTA1) is the major actin in postnatal skeletal muscle. Mutations of ACTA1 cause mostly fatal congenital myopathies. Cardiac α-actin (ACTC) is the major striated actin in adult heart and fetal skeletal muscle. It is unknown why ACTC and ACTA1 expression switch during development. We investigated whether ACTC can replace ACTA1 in postnatal skeletal muscle. Two ACTC transgenic mouse lines were crossed with Acta1 knockout mice (which all die by 9 d after birth). Offspring resulting from the cross with the high expressing line survive to old age, and their skeletal muscles show no gross pathological features. The mice are not impaired on grip strength, rotarod, or locomotor activity. These findings indicate that ACTC is sufficiently similar to ACTA1 to produce adequate function in postnatal skeletal muscle. This raises the prospect that ACTC reactivation might provide a therapy for ACTA1 diseases. In addition, the mouse model will allow analysis of the precise functional differences between ACTA1 and ACTC

DNA sense-and-respond protein modules for mammalian cells

We generated synthetic protein components that can detect specific DNA sequences and subsequently trigger a desired intracellular response. These modular sensors exploit the programmability of zinc-finger DNA recognition to drive the intein-mediated splicing of an artificial trans-activator that signals to a genetic circuit containing a given reporter or response gene. We used the sensors to mediate sequence recognition−induced apoptosis as well as to detect and report a viral infection. This work establishes a synthetic biology framework for endowing mammalian cells with sentinel capabilities, which provides a programmable means to cull infected cells. It may also be used to identify positively transduced or transfected cells, isolate recipients of intentional genomic edits and increase the repertoire of inducible parts in synthetic biology.United States. Defense Advanced Research Projects Agency (DARPA-BAA-11-23)Defense Threat Reduction Agency (DTRA) (HDTRA1-14-1-0006)United States. Air Force Office of Scientific Research (FA9550-14-1-0060