Energy matters: mitochondrial proteomics for biomedicine

This review compiles results of medical relevance from mitochondrial proteomics, grouped either according to the type of disease - genetic or degenerative - or to the involved mechanism - oxidative stress or apoptosis. The findings are commented in the light of our current understanding of uniformity/variability in cell responses to different stimuli. Specificities in the conceptual and technical approaches to human mitochondrial proteomics are also outlined.     

Hospitalization Rates and Post-Operative Mortality for Abdominal Aortic Aneurysm in Italy over the Period 2000–2011

Background

Recent studies have reported declines in incidence, prevalence and mortality for abdominal aortic aneurysms (AAAs) in various countries, but evidence from Mediterranean countries is lacking. The aim of this study is to examine the trend of hospitalization and post-operative mortality rates for AAAs in Italy during the period 2000–2011, taking into account the introduction of endovascular aneurysm repair (EVAR) in 1990s.

Methods

This retrospective cohort study was carried out in Emilia-Romagna, an Italian region with 4.5 million inhabitants. A total of 19,673 patients hospitalized for AAAs between 2000 and 2011, were identified from the hospital discharge records (HDR) database. Hospitalization rates, percentage of OSR and EVAR and 30-day mortality rates were calculated for unruptured (uAAAs) and ruptured AAAs (rAAAs).

Results

Adjusted hospitalization rates decreased on average by 2.9% per year for uAAAs and 3.2% for rAAAs (p<0.001). The temporal trend of 30-day mortality rates remained stable for both groups. The percentage of EVAR for uAAAs increased significantly from 2006 to 2011 (42.7 versus 60.9% respectively, mean change of 3.9% per year, p<0.001). No significant difference in mortality was found between OSR and EVAR for uAAAs and rAAAs.

Conclusions

The incidence and trend of hospitalization rates for rAAAs and uAAAs decreased significantly in the last decade, while 30-day mortality rates in operated patients remained stable. OSR continued to be the most common surgery in rAAAs, although the gap between OSR and EVAR recently declined. The EVAR technique became the preferred surgery for uAAAs since 2008.     

Inflammatory serum proteome pattern in mice fed a high-fat diet

To investigate the influence of diet on serum protein pattern, mice were fed for 8 weeks either control chow or a high-fat diet (containing 21 % w/w milk fat and 0.2 % w/w cholesterol); sera were collected and analyzed by 2-DE. The main positive acute-phase reactant proteins, haptoglobin and hemopexin, were significantly up-regulated in animals receiving the high-fat diet. Data on all other proteins also pointed to an inflammatory condition in these animals. The largest change in concentration was observed for carboxylesterase N, a circulating enzyme seldom connected with lipid metabolism in earlier reports. These observations agree with the notion of a link between diet-induced hyperlipidemia and the inflammatory component of its cardiovascular sequels in humans, but the effects in the experimental animals are massive and obviously affect most of the major serum proteins.     

Age-Related Circadian Rhythm of DHEAS Plasma Levels in Male Subjects

The aging influences the endocrine temporal structure, including DHEAS which can be considered as a biomarker of aging, since its levels gradually decrease in older subjects. The aim of this work was to observe the circadian rhythms of DHEAS, prolactin, cortisol and body temperature, in healthy elderly male subjects (73.7 ± 2.5 years) compared with healthy young subjects (27.2 ± 6.6 years). The results documented that in our subjects no significant age-related differences in prolactin levels existed. In elderly subjects cortisol levels were weakly enhanced in comparison with young subjects. DHEAS showed a preserved circadian rhythm, but markedly lower rhythm adjusted mean (74.38 ± 10.29 versus 273.63 ± 26.39) (p &lt; 0.001) and decreased amplitude of oscillation (p &lt; 0.001), when expressed as absolute value, in elderly subjects when compared with young subjects. In elderly subjects the DHEAS circadian rhythm modifications could represent an impairment of of the endocrine temporal structure.     

The Mitochondrial Na+/Ca2+ Exchanger Upregulates Glucose Dependent Ca2+ Signalling Linked to Insulin Secretion

Mitochondria mediate dual metabolic and Ca²⁺ shuttling activities. While the former is required for Ca²⁺ signalling linked to insulin secretion, the role of the latter in β cell function has not been well understood, primarily because the molecular identity of the mitochondrial Ca²⁺ transporters were elusive and the selectivity of their inhibitors was questionable. This study focuses on NCLX, the recently discovered mitochondrial Na⁺/Ca²⁺ exchanger that is linked to Ca²⁺ signalling in MIN6 and primary β cells. Suppression either of NCLX expression, using a siRNA construct (siNCLX) or of its activity, by a dominant negative construct (dnNCLX), enhanced mitochondrial Ca²⁺ influx and blocked efflux induced by glucose or by cell depolarization. In addition, NCLX regulated basal, but not glucose-dependent changes, in metabolic rate, mitochondrial membrane potential and mitochondrial resting Ca²⁺. Importantly, NCLX controlled the rate and amplitude of cytosolic Ca²⁺ changes induced by depolarization or high glucose, indicating that NCLX is a critical and rate limiting component in the cross talk between mitochondrial and plasma membrane Ca²⁺ signalling. Finally, knockdown of NCLX expression was followed by a delay in glucose-dependent insulin secretion. These findings suggest that the mitochondrial Na⁺/Ca²⁺ exchanger, NCLX, shapes glucose-dependent mitochondrial and cytosolic Ca²⁺ signals thereby regulating the temporal pattern of insulin secretion in β cells.