Current scientific debates center on the impact of lipids and mitochondrial function on diverse aspects of human health, nutrition and disease, among them the association of lipotoxicity with the onset of insulin resistance in skeletal muscle, and with heart dysfunction in obesity and diabetes. Mitochondria play a fundamental role in aging and in prevalent acute or chronic diseases. Lipids are main mitochondrial fuels however these molecules can also behave as uncouplers and inhibitors of oxidative phosphorylation. Knowledge about the functional composition of these contradictory effects and their impact on mitochondrial-cellular energetics/redox status is incomplete. Cells store fatty acids (FAs) as triacylglycerol and package them into cytoplasmic lipid droplets (LDs). New emerging data shows the LD as a highly dynamic storage pool of FAs that can be used for energy reserve. Lipid excess packaging into LDs can be seen as an adaptive response to fulfilling energy supply without hindering mitochondrial or cellular redox status and keeping low concentration of lipotoxic intermediates. Herein we review the mechanisms of action and utilization of lipids by mitochondria reported in liver, heart and skeletal muscle under relevant physiological situations, e.g., exercise. We report on perilipins, a family of proteins that associate with LDs in response to loading of cells with lipids. Evidence showing that in addition to physical contact, mitochondria and LDs exhibit metabolic interactions is presented and discussed. A hypothetical model of channeled lipid utilization by mitochondria is proposed. Direct delivery and channeled processing of lipids in mitochondria could represent a reliable and efficient way to maintain reactive oxygen species (ROS) within levels compatible with signaling while ensuring robust and reliable energy supply.

Bhatt NM, Aon MA, Tocchetti CG, Shen X, Dey S, Ramirez-Correa G, O=Rourke B, Gao WD, Cortassa S. Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose. Am J Physiol Heart Circ Physiol 308: H291-H302, 2015. First published December 3, 2014; doi:10.1152/ajpheart.00378.2014.-Hearts from type 2 diabetic (T2DM) subjects are chronically subjected to hyperglycemia and hyperlipidemia, both thought to contribute to oxidizing conditions and contractile dysfunction. How redox alterations and contractility interrelate, ultimately diminishing T2DM heart function, remains poorly understood. Herein we tested whether the fatty acid palmitate (Palm), in addition to its energetic contribution, rescues function by improving redox [glutathione (GSH), NAD(P)H, less oxidative stress] in T2DM rat heart trabeculae subjected to high glucose. Using cardiac trabeculae from Zucker Diabetic Fatty (ZDF) rats, we assessed the impact of low glucose (EG) and high glucose (HG), in absence or presence of Palm or insulin, on force development, energetics, and redox responses. We found that in EG ZDF and lean trabeculae displayed similar contractile work, yield of contractile work (Ycw), representing the ratio of force time integral over rate of O2 consumption. Conversely, HG had a negative impact on Ycw, whereas Palm, but not insulin, completely prevented contractile loss. This effect was associated with higher GSH, less oxidative stress, and augmented matrix GSH/thioredoxin (Trx) in ZDF mitochondria. Restoration of myocardial redox with GSH ethyl ester also rescued ZDF contractile function in HG, independently from Palm. These results support the idea that maintained redox balance, via increased GSH and Trx antioxidant activities to resist oxidative stress, is an essential protective response of the diabetic heart to keep contractile function. contractile work; rate of respiration; redox environment; antioxidant systems; oxidative phosphorylation; mitochondrial ros emission; Zucker diabetic fatty rat A COMMON COMPLICATION OF TYPE 2 diabetes mellitus (T2DM) is cardiomyopathy, characterized by diastolic and systolic dysfunction, which is likely impacted by alterations in metabolic substrate availability. Although the healthy heart is flexible regarding fuel selection, the high levels of glucose and fat in T2DM lead to questions about which factors contribute to dysfunction and which are beneficial as energy source or redox donors (35).Fatty acids (FA) and glucose are the two major fuels driving heart contraction, and in T2DM and obesity existing evidence indicates increased FA oxidation (12, 15). The idea that FAs excess negatively regulates glucose oxidation in diabetes according to the Randle mechanism (33) remains a central postulate explaining some negative consequences of substrate shift in this metabolic disorder. However, it is now increasingly appreciated that hyperglycemia per se can trigger cellular damage, independently from FA utilization (11). The multiple mechanisms throug...

Significance: The heart depends on continuous mitochondrial ATP supply and maintained redox balance to properly develop force, particularly under increased workload. During diabetes, however, myocardial energeticredox balance is perturbed, contributing to the systolic and diastolic dysfunction known as diabetic cardiomyopathy (DC). Critical Issues: How these energetic and redox alterations intertwine to influence the DC progression is still poorly understood. Excessive bioavailability of both glucose and fatty acids (FAs) play a central role, leading, among other effects, to mitochondrial dysfunction. However, where and how this nutrient excess affects mitochondrial and cytoplasmic energetic/redox crossroads remains to be defined in greater detail. Recent Advances: We review how high glucose alters cellular redox balance and affects mitochondrial DNA. Next, we address how lipid excess, either stored in lipid droplets or utilized by mitochondria, affects performance in diabetic hearts by influencing cardiac energetic and redox assets. Finally, we examine how the reciprocal energetic/redox influence between mitochondrial and cytoplasmic compartments shapes myocardial mechanical activity during the course of DC, focusing especially on the glutathione and thioredoxin systems. Future Directions: Protecting mitochondria from losing their ability to generate energy, and to control their own reactive oxygen species emission is essential to prevent the onset and/or to slow down DC progression. We highlight mechanisms enforced by the diabetic heart to counteract glucose/FAs surplus-induced damage, such as lipid storage, enhanced mitochondria-lipid droplet interaction, and upregulation of key antioxidant enzymes. Learning more on the nature and location of mechanisms sheltering mitochondrial functions would certainly help in further optimizing therapies for human DC. Antioxid. Redox Signal. 22, 1563-1586. Mitochondria and Heart FunctionRedox and energetics of heart function T he heart depends on continuous oxidative metabolism to maintain ATP supply and redox balance for optimal contractile function. More than 90% of heart metabolism is aerobic (166,180). A 70 kg human male at rest consumes 430 L of O 2 per day (177), which can increase 5-to 10-fold depending on physical activity (207). About 90% of this O 2 will be channeled to mitochondrial respiration (166); about 10% of O 2 usage is nonmitochondrial (79). Consequently, mitochondria are central to aerobic life, and their energetic and redox functions are pivotal for health, disease, and aging (36,69,107).Cardiac output measures heart effectiveness as a pump; it can be calculated by multiplying the heart rate (beats/min) by stroke volume (ml/beat). For an average resting heart rate of 72 beats/min and a stroke volume of 70 ml/beat, the cardiac output is *5 L/min. In humans, the average total blood volume is about 5 L; therefore, at rest, one side of the heart pumps all the blood in the body in 1 min (177). The in vivo rate of cardiac basal metabolism is 5-10 time...

The mechanism of testicular toxicity of lead (Pb) and cadmium (Cd) is poorly understood. Previous studies focused on single metal-related changes in testicular toxicity. This study points towards the possible involvement of Pb- and Cd-induced oxidative stress in the suppression of steroidogenesis. The oxidative status of testis of adult male rats exposed to Pb acetate and cadmium acetate either alone or in combination at a dose of 0.025 mg kg(-1) body weight of metal intraperitoneally for 15 days was studied. Pb and Cd caused an increase in reactive oxygen species (ROS) by elevating testicular malondialdehydes (MDA) and decrease in activities of testicular antioxidant enzymes superoxide dismutase (SOD), catalase, glucose 6 phosphate dehydrogenase (G6PDH) and glutathione-S-transferase (GST) in mitochondrial and/or post-mitochondrial fraction. Activities of steroidogenic enzymes 3β and 17β-hydroxysteroid dehydrogenase also decreased significantly leading to altered testosterone production. Metal-exposed groups showed significantly decreased testicular and epididymal sperm count. Epididymal sperm motility and viability was also decreased on Pb and Cd exposure. Cd exposure showed more toxic effect than lead exposure, while combined exposure demonstrated least toxicity. In vitro experiments showed that vitamin C restores steroidogenic enzyme activities, suggesting that Pb- and Cd-induced ROS inhibits the testicular steroidogenesis.

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Bioclastic carbonate deposits that formed because of a combination of nearshore marine, fluvial, and aeolian processes, occur along the Saurashtra coast and in the adjacent interior regions of western India. Whether these carbonates formed by marine or aeolian processes has been debated for many decades. The presence of these deposits inland poses questions as to whether they are climate controlled or attributable to postdepositional tectonic uplift. In particular, the debate centres on chronologic issues including (1) appropriate sampling strategies and (2) the use of 230Th/234U and 14C ages on the bulk carbonates. Using traces (<1%) of quartz grains trapped in carbonate matrices, optically stimulated luminescence (OSL) dating of quartz grains, deposited along with the carbonate grains, provides ages for the most recent deposition events. The OSL ages range from >165 to 44 ka for the shell limestones, 75–17 ka for the fluvially reworked sheet deposits, and 80–11 ka for miliolites deposited by aeolian processes. These are younger than the 230Th/234U and 14C ages and suggest that the inland carbonate deposits were reworked from older carbonate sediments that were transported during more arid phases.

Objective To describe the risk and risk factors for ocular hypertension (OHT) in adults with non-infectious uveitis. Design Retrospective, multicenter, cohort study. Participants Patients aged ≥ 18 years with non-infectious uveitis seen between 1979 and 2007 at 5 tertiary uveitis clinics. Methods Demographic, ocular and treatment data were extracted from medical records of uveitis cases. Main outcome measures Prevalent and incident OHT with intraocular pressures (IOP) of ≥21 mmHg, ≥30mmHg and rise of ≥10 mmHg from documented IOP recordings (or use of treatment for OHT). Results Among 5270 uveitic eyes of 3308 patients followed for OHT, the mean annual incidence rates for OHT ≥21mmHg and OHT ≥30mmHg are 14.4% (95%CI: 13.4%, 15.5%) and 5.1% (95% CI: 4.7%, 5.6%) per year, respectively. Statistically significant risk factors for incident OHT ≥30mmHg included: systemic hypertension (adjusted hazard ratio (aHR) = 1.29); worse presenting visual acuity (20/200 or worse vs 20/40 or better, aHR = 1.47); pars plana vitrectomy (aHR = 1.87); prior history of OHT in the other eye: IOP ≥ 21 mmHg (aHR = 2.68), ≥30 mmHg (aHR=4.86), and prior/current use of IOP-lowering drops or surgery in the other eye (aHR = 4.17); anterior chamber cells: 1+ (aHR = 1.43) and ≥2+ (aHR = 1.59) vs none; epiretinal membrane (aHR=1.25); peripheral anterior synechiae (aHR = 1.81); current use of prednisone>7.5 mg/day (aHR = 1.86); periocular corticosteroids in the last three months (aHR = 2.23); current topical corticosteroid use [≥ 8X/day vs. none] (aHR=2.58); and prior use of fluocinolone acetonide implants (aHR = 9.75). Bilateral uveitis (aHR = 0.69) and previous hypotony (aHR=0.43) were associated with statistically significantly lower risk of OHT. Conclusions OHT is sufficiently common in eyes treated for uveitis that surveillance for OHT is essential at all visits for all cases. Patients with one or more of the several risk factors identified are at particularly high risk, and must be carefully managed. Modifiable risk factors, such as use of corticosteroids, suggest opportunities to reduce OHT risk, within the constraints of the overriding need to control the primary ocular inflammatory disease.

Geomorphic expression of land-sea interaction is preserved in the form of abandoned cliffs, marine terraces, shore platforms and marine notches along the southern Saurashtra coast. These features have been used to ascertain the magnitude of sea level changes during late Quaternary. Notch morphology and associated biological encrustation have been used to estimate the magnitude and duration of palaeo-sea strands. Marine notches and other erosive features occurring between 12 and 15 m above the present Biological Mean Sea Level (BMSL) are attributed to the last interglacial corresponding to the Marine Isotopic Stage 5 (MIS-5). However, 6 to 9 m upliftment of the coastal fringe is attributed to this sea level. The second major high sea strand was identified during the mid-Holocene when the sea rose 2 m above the present level. Notches corresponding to this high sea level are recorded 4 to 5 m above the present BMSL.