Novel Mitochondrial Substrates of Omi Indicate a New Regulatory Role in Neurodegenerative Disorders

The mitochondrial protease OMI (also known as HtrA2) has been implicated in Parkinson's Disease (PD) and deletion or protease domain point mutations have shown profound neuropathologies in mice. A beneficial role by OMI, in preserving cell viability, is assumed to occur via the avoidance of dysfunctional protein turnover. However relatively few substrates for mitochondrial Omi are known. Here we report our identification of three novel mitochondrial substrates that impact metabolism and ATP production. Using a dual proteomic approach we have identified three interactors based upon ability to bind to OMI, and/or to persist in the proteome after OMI activity has been selectively inhibited. One candidate, the chaperone HSPA8, was common to each independent study. Two others (PDHB subunit and IDH3A subunit) did not appear to bind to OMI, however persisted in the mito-proteome when OMI was inhibited. Pyruvate dehydrogenase (PDH) and isocitrate dehydrogenase (IDH) are two key Kreb's cycle enzymes that catalyse oxidative decarboxylation control points in mitochondrial respiration. We verified both PDHB and IDH3A co-immunoprecipitate with HSPA8 and after elution, were degraded by recombinant HtrA2 in vitro. Additionally our gene expression studies, using rotenone (an inhibitor of Complex I) showed Omi expression was silenced when pdhb and idh3a were increased when a sub-lethal dose was applied. However higher dose treatment caused increased Omi expression and decreased levels of pdhb and idh3a transcripts. This implicates mitochondrial OMI in a novel mechanism relating to metabolism

The mitochondrial serine protease HtrA2/Omi: an overview

The HtrA family refers to a group of related oligomeric serine proteases that combine a trypsin-like protease domain with at least one PDZ interaction domain. Mammals encode four HtrA proteases, named HtrA1-4. The protease activity of the HtrA member HtrA2/Omi is required for mitochondrial homeostasis in mice and humans and inactivating mutations associated with neurodegenerative disorders such as Parkinson's disease. Moreover, HtrA2/Omi is released in the cytosol, where it contributes to apoptosis through both caspase-dependent and -independent pathways. Here, we review the current knowledge of HtrA2/Omi biology and discuss the signaling pathways that underlie its mitochondrial and apoptotic functions from an evolutionary perspective

Seasonal variations in cardiovascular disease

Cardiovascular disease (CVD) follows a seasonal pattern in many populations. Broadly defined winter peaks and clusters of all subtypes of CVD after 'cold snaps' are consistently described, with corollary peaks linked to heat waves. Individuals living in milder climates might be more vulnerable to seasonality. Although seasonal variation in CVD is largely driven by predictable changes in weather conditions, a complex interaction between ambient environmental conditions and the individual is evident. Behavioural and physiological responses to seasonal change modulate susceptibility to cardiovascular seasonality. The heterogeneity in environmental conditions and population dynamics across the globe means that a definitive study of this complex phenomenon is unlikely. However, given the size of the problem and a range of possible targets to reduce seasonal provocation of CVD in vulnerable individuals, scope exists for both greater recognition of the problem and application of multifaceted interventions to attenuate its effects. In this Review, we identify the physiological and environmental factors that contribute to seasonality in nearly all forms of CVD, highlight findings from large-scale population studies of this phenomenon across the globe, and describe the potential strategies that might attenuate peaks in cardiovascular events during cold and hot periods of the year.Simon Stewart, Ashley K. Keates, Adele Redfern and John J. V. McMurra

Seasonal variations in cardiovascular disease

Cardiovascular disease (CVD) follows a seasonal pattern in many populations. Broadly defined winter peaks and clusters of all subtypes of CVD after 'cold snaps' are consistently described, with corollary peaks linked to heat waves. Individuals living in milder climates might be more vulnerable to seasonality. Although seasonal variation in CVD is largely driven by predictable changes in weather conditions, a complex interaction between ambient environmental conditions and the individual is evident. Behavioural and physiological responses to seasonal change modulate susceptibility to cardiovascular seasonality. The heterogeneity in environmental conditions and population dynamics across the globe means that a definitive study of this complex phenomenon is unlikely. However, given the size of the problem and a range of possible targets to reduce seasonal provocation of CVD in vulnerable individuals, scope exists for both greater recognition of the problem and application of multifaceted interventions to attenuate its effects. In this Review, we identify the physiological and environmental factors that contribute to seasonality in nearly all forms of CVD, highlight findings from large-scale population studies of this phenomenon across the globe, and describe the potential strategies that might attenuate peaks in cardiovascular events during cold and hot periods of the year