Improved Mitochondrial Stress Response in Long-lived Snell Dwarf Mice

Upregulation of the mitochondrial unfolded protein response (mtUPR) as a result of alterations in mitochondrial protein stoichiometry has been proposed as a common pathway in longevity. While mtUPR upregulation correlates with lifespan extension in lower organisms, it is not known whether mtUPR is elevated in long-lived mice. We hypothesized that long-lived mutant mouse models would have enhanced mtUPR. We found that Snell dwarf mice ("Snell mice"), one of the longest-lived mouse models with 30-40% lifespan extension, exhibit augmented mitochondrial stress response. Primary fibroblasts from Snell mice show elevated levels of the mitochondrial chaperone HSP60 and mitochondrial protease LONP1, two components of the mtUPR. In response to mitochondrial stress, the increase in the expression of Tfam, a regulator of mitochondrial transcription, is higher in Snell cells, while Pgc-1α, the main regulator of mitochondrial biogenesis, is upregulated only in Snell cells. Consistent with these differences, after exposure to mitochondrial stress by doxycycline treatment, oxidative respiration rate and cellular ATP content, indicators of mitochondrial function, are higher in Snell cells than those in normal cells. In vivo, Snell mice show robust mtUPR induction after mitochondrial stress exposure by doxycycline treatment, as demonstrated by a 40-50% increase in HSP60 and LONP1 protein levels in liver tissue samples. In contrast, normal mice fail to show such a response despite exhibiting aggravated disturbance of mitochondrial protein stoichiometry. We noted elevated protein levels of LONP1 and TFAM in Snell liver without comparable increases in corresponding mRNA levels, suggesting an upregulation at the translational level. Based on recent findings showing that mRNA transcripts bearing 5'UTR N6-methyladenosine (m6A) modifications are selectively translated by m6A-mediated cap-independent translation (m6A-CIT), we hypothesized that LONP1 and TFAM protein levels may be elevated through m6A-CIT. Consistent with our hypothesis, Lonp1, Tfam, and Pgc-1α carry the consensus motif for m6A modification, and are listed among putative targets of m6A-CIT. We found that liver, kidney, and skeletal muscle of Snell mice have elevated protein levels of METTL3 and METTL14, which add m6A marks to target mRNAs, and of YTHDF1 and YTHDF2, which promote translation of m6A-tagged mRNAs. In contrast, ALKBH5 and FTO, which downregulate cap-independent translation of target transcripts by removing m6A marks, are not upregulated. By knocking-down METTL3 in HEK 293 cells, we demonstrated that protein levels of TFAM and PGC-1α, but not of LONP1, are regulated by m6A-CIT. These findings support the hypothesis that the m6A-CIT pathway is upregulated and might contribute to upregulation of TFAM and PGC-1α in Snell mice. Our work demonstrates improved mitochondrial stress response in a long-lived mouse model, and provides a rationale for future mouse lifespan studies involving compounds that induce mtUPR. Our data indicating upregulation of the m6A-CIT pathway in Snell mice support the hypothesis that m6A-CIT may partially account for elevated protein levels of TFAM and PGC-1α.PHDMolecular & Cellular PathologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/147485/1/ozkurede_1.pd

Immunology in clinic review series; focus on autoinflammatory diseases: role of inflammasomes in autoinflammatory syndromes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90366/1/j.1365-2249.2011.04535.x.pd

Neutrophil-Lymphocyte Ratio in Patients With Familial Mediterranean Fever

BackgroundBlood neutrophil-to-lymphocyte (N/L) ratio is an indicator of the overall inflammatory status of the body, and an alteration in N/L ratio may be found in patients with familial Mediterranean fever (FMF). The aim of this study was to investigate the interrelationship between N/L ratio and FMF

Cryopyrin-associated periodic syndrome in Australian children and adults: Epidemiological, clinical and treatment characteristics.

AIM: Cryopyrin-associated periodic syndromes (CAPS) encapsulate three auto-inflammatory conditions, ranging in severity from mild (familial cold auto-inflammatory syndrome: FCAS), moderate (Muckle-Wells syndrome: MWS) and severe (neonatal onset multi-inflammatory disorder: NOMID). We aimed to describe the epidemiology, clinical features and outcomes of Australian children and adults with CAPS. METHODS: Patients were identified and clinical data collected through a questionnaire sent during 2012-2013 to clinicians reporting to the Australian Paediatric Surveillance Unit and subscribing to the Australasian Societies for Allergy/Immunology, Rheumatology and Dermatology. RESULTS: Eighteen cases of CAPS were identified (8 NOMID; 8 MWS, 2 FCAS); 12 in children <18 years of age. The estimated population prevalence of CAPS was 1 per million persons. Diagnostic delay was frequent, particularly in those with milder phenotypes (median diagnostic delay in MWS/FCAS 20.6 years compared with NOMID 2.1 years; P = 0.04). Common presenting features included urticaria (100%), periodic fever (78%), arthralgia (72%) and sensorineural hearing loss (61%). Almost all (90%) MWS patients had a family member similarly affected compared with none in the NOMID group (P = 0.004). A significant proportion of patients on anti-interleukin (IL)-1 therapy (n = 13) no longer had systemic inflammation. Only 50% with sensorineural hearing loss had hearing restored on anti-IL-1 therapy. CONCLUSIONS: Although CAPS are rare, patients often endured prolonged periods of systemic inflammation. This is despite almost all MWS patients having family members with similar symptoms and children with NOMID presenting with chronic infantile urticaria associated with multi-system inflammation. Hearing loss in NOMID/MWS was frequent, and reversible in only 50% of cases