Summary Mitochondria require nicotinamide adenine dinucleotide (NAD + ) in order to carry out the fundamental processes that fuel respiration and mediate cellular energy transduction. Mitochondrial NAD + transporters have been identified in yeast and plants 1 , 2 but their very existence is controversial in mammals 3 – 5 . Here we demonstrate that mammalian mitochondria are capable of taking up intact NAD + and identify SLC25A51 (an essential 6 , 7 mitochondrial protein of previously unknown function, also known as MCART1) as a mammalian mitochondrial NAD + transporter. Loss of SLC25A51 decreases mitochondrial but not whole-cell NAD + content, impairs mitochondrial respiration, and blocks the uptake of NAD + into isolated mitochondria. Conversely, overexpression of SLC25A51 or a nearly identical paralog, SLC25A52, increases mitochondrial NAD + levels and restores NAD + uptake into yeast mitochondria lacking endogenous NAD + transporters. Together, these findings identify SLC25A51 as the first transporter capable of importing NAD + into mammalian mitochondria.

No abstract

Brain metastasis, the most lethal form of melanoma and carcinoma, is the consequence of favorable interactions between the invading cancer cells and the brain cells. Peroxisome proliferator-activated receptor γ (PPARγ) has ambiguous functions in cancer development, and its relevance in advanced brain metastasis remains unclear. Here, we demonstrate that astrocytes, the unique brain glial cells, activate PPARγ in brain metastatic cancer cells. PPARγ activation enhances cell proliferation and metastatic outgrowth in the brain. Mechanistically, astrocytes have a high content of polyunsaturated fatty acids that act as "donors" of PPARγ activators to the invading cancer cells. In clinical samples, PPARγ signaling is signifi cantly higher in brain metastatic lesions. Notably, systemic administration of PPARγ antagonists signifi cantly reduces brain metastatic burden in vivo. Our study clarifi es a prometastatic role for PPARγ signaling in cancer metastasis in the lipid-rich brain microenvironment and argues for the use of PPARγ blockade to treat brain metastasis. SIGNIFICANCE: Brain-tropic cancer cells take advantage of the lipid-rich brain microenvironment to facilitate their proliferation by activating PPARγ signaling. This protumor effect of PPARγ in advanced brain metastases is in contrast to its antitumor function in carcinogenesis and early metastatic steps, indicating that PPARγ has diverse functions at different stages of cancer development.

Diseases associated with mitochondrial DNA (mtDNA) mutations are highly variable in phenotype, in large part because of differences in the percentage of normal and mutant mtDNAs (heteroplasmy) present within the cell. For example, increasing heteroplasmy levels of the mtDNA tRNALeu(UUR) nucleotide (nt) 3243A > G mutation result successively in diabetes, neuromuscular degenerative disease, and perinatal lethality. These phenotypes are associated with differences in mitochondrial function and nuclear DNA (nDNA) gene expression, which are recapitulated in cybrid cell lines with different percentages of m.3243G mutant mtDNAs. Using metabolic tracing, histone mass spectrometry, and NADH fluorescence lifetime imaging microscopy in these cells, we now show that increasing levels of this single mtDNA mutation cause profound changes in the nuclear epigenome. At high heteroplasmy, mitochondrially derived acetyl-CoA levels decrease causing decreased histone H4 acetylation, with glutamine-derived acetyl-CoA compensating when glucose-derived acetyl-CoA is limiting. In contrast, α-ketoglutarate levels increase at midlevel heteroplasmy and are inversely correlated with histone H3 methylation. Inhibition of mitochondrial protein synthesis induces acetylation and methylation changes, and restoration of mitochondrial function reverses these effects. mtDNA heteroplasmy also affects mitochondrial NAD+/NADH ratio, which correlates with nuclear histone acetylation, whereas nuclear NAD+/NADH ratio correlates with changes in nDNA and mtDNA transcription. Thus, mutations in the mtDNA cause distinct metabolic and epigenomic changes at different heteroplasmy levels, potentially explaining transcriptional and phenotypic variability of mitochondrial disease.

Ipilimumab (Yervoy®) is an anti-cytotoxic T-lymphocyte antigen (CTLA)-4 monoclonal antibody that has been approved in the US for the first- or second-line treatment of patients with malignant melanoma. In the EU, it is awaiting approval as second-line therapy for melanoma. Ipilimumab blocks the effects of the negative T-cell regulator CTLA-4, which may in turn augment T-cell responses to tumour cells. Preclinical studies have indicated that antibody blocking of CTLA-4 can lead to potent immune responses. Ipilimumab is also in development as first- and second-line therapy for prostate cancer where it has progressed to phase III clinical trials worldwide, and it is in phase II development for non-small cell lung cancer. Ipilimumab was originated by the University of California, Berkeley, in the US and subsequently licensed to Medarex, which was later acquired by Bristol-Myers Squibb. This article summarizes the milestones in the development of intravenous ipilimumab leading to this first approval. This profile has been extracted from Wolters Kluwer's R&D Insight drug pipeline database. R&D Insight tracks drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch.