Background. Sepsis is associated with mitochondrial dysfunction and impaired oxygen consumption, which may condition clinical outcome independent of tissue oxygenation. However, mitochondrial role in sepsis severity remains unknown. We aimed to characterize mitochondrial function in sepsis, establish its origin and cellular consequences, and determine its correlation with clinical symptoms and outcome. Methods. Different markers of mitochondrial activity, nitrosative and oxidative stress, apoptosis, and inflammation were measured in peripheral blood mononuclear cells (PBMCs) and plasma of 19 septic patients and 20 controls. Plasma capacity to induce mitochondrial dysfunction was assessed in muscle mitochondria from 5 healthy individuals incubated with plasma of septic patients or controls. Results. Despite unaltered mitochondrial mass and protein synthesis, enzymatic mitochondrial complexes I, III, and IV and oxygen consumption were significantly inhibited in sepsis. Septic plasma tended to reduce oxygen consumption of healthy mitochondria and showed significantly increased amounts of extracellular mitochondrial DNA and inflammatory cytokines, especially in patients presenting adverse outcome. Active nuclear factor kappa-light-chain enhancer of activated B cells (NFKB) was also significantly increased, together with nitric oxide, oxidative stress and apoptosis. Additionally, sepsis severity significantly correlated with complex I inhibition, NFKB activation and intercellular adhesion molecule expression. Conclusions. A plasmatic factor such as nitric oxide, increased in inflammation and able to induce mitochondrial dysfunction, oxidative stress and apoptosis, may be responsible for cell damage in sepsis. Together with bacterial infection, leakage of mitochondrial DNA from damaged cells into circulation could contribute to systemic inflammatory response syndrome. Mitochondrial dysfunction and inflammation correlate with sepsis severity and outcome, becoming targets for supporting therapies.

The distinguishing pathogenic features of neurodegenerative diseases include mitochondrial dysfunction and derived reactive oxygen species generation. The neural tissue is highly sensitive to oxidative stress and this is a prominent factor in both chronic and acute neurodegeneration. Based on this, therapeutic strategies using antioxidant molecules towards redox equilibrium have been widely used for the treatment of several brain pathologies. Globally, polyphenols, carotenes and vitamins are among the most typical exogenous antioxidant agents that have been tested in neurodegeneration as adjunctive therapies. However, other types of antioxidants, including hormones, such as the widely used melatonin, are also considered neuroprotective agents and have been used in different neurodegenerative contexts. This review highlights the most relevant mitochondrial antioxidant targets in the main neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease and also in the less represented amyotrophic lateral sclerosis, as well as traumatic brain injury, while summarizing the latest randomized placebo-controlled trials.

Objective: Antiretrovirals, especially thymidine-analogue nucleoside reverse transcriptase inhibitors (tNRTIs), may cause the mitochondrial damage in adipose tissue that has been associated with lipodystrophy development. HIV itself may damage blood cell mitochondria. However, the viral capacity to induce adipose tissue mitochondrial lesion is still a matter of doubt. We aimed to assess whether untreated HIV infection was associated with adipose tissue mitochondrial abnormalities. Design: Single-site, cross-sectional, controlled observational and exploratory study without intervention. Methods: We included 24 uninfected controls and 18 HIV-infected patients with undetectable viral load and no clinical signs of lipodystrophy stratified as antiretroviral naive (n = 11) or at least 6-month antiviral-treated with a double NRTI combination, including lamivudine plus one tNRTI (n = 7). Subcutaneous adipose tissue was homogenated to determine mtDNA content by rtPCR and mitochondrial function per mitochondria through the spectrophotometric measurement of cytochrome c oxidase activity normalized by citrate synthase amount (COX/citrate synthase). Differences in mitochondrial parameters among groups were sought to determine the contribution of HIV and antiretrovirals to mitochondrial alterations. Results: Compared with uninfected controls (arbitrarily assigned 100%), naive individuals presented a marked decrease in adipose tissue mtDNA content and COX/citrate synthase function (62 and 75% remaining content/activity, P < 0.001 and P < 0.05). Antiretrovirals did not increase this impairment (69 and 70% remaining content/activity, P < 0.05 compared to controls and P = not significant compared to naives). Additionally, molecular and functional mitochondrial parameters were positively correlated (P < 0.05). Conclusion: In nonlipodystrophic HIV-infected naive patients, viral infection is associated with adipose tissue mtDNA decrease and mitochondrial dysfunction independently of antiretroviral treatment.

Sporadic inclusion body myositis (sIBM) is one of the most common myopathies in elderly people. Mitochondrial abnormalities at the histological level are present in these patients. We hypothesize that mitochondrial dysfunction may play a role in disease aetiology. We took the following measurements of muscle and peripheral blood mononuclear cells (PBMCs) from 30 sIBM patients and 38 age- and gender-paired controls: mitochondrial DNA (mtDNA) deletions, amount of mtDNA and mtRNA, mitochondrial protein synthesis, mitochondrial respiratory chain (MRC) complex I and IV enzymatic activity, mitochondrial mass, oxidative stress and mitochondrial dynamics (mitofusin 2 and optic atrophy 1 levels). Depletion of mtDNA was present in muscle from sIBM patients and PBMCs showed deregulated expression of mitochondrial proteins in oxidative phosphorylation. MRC complex IV/citrate synthase activity was significantly decreased in both tissues and mitochondrial dynamics were affected in muscle. Depletion of mtDNA was significantly more severe in patients with mtDNA deletions, which also presented deregulation of mitochondrial fusion proteins. Imbalance in mitochondrial dynamics in muscle was associated with increased mitochondrial genetic disturbances (both depletion and deletions), demonstrating that proper mitochondrial turnover is essential for mitochondrial homoeostasis and muscle function in these patients.

Highly active antiretroviral therapy (HAART) has decreased the risk of HIV mother-to-child transmission. However, HIV and HAART have been associated with adverse perinatal outcome. HAART has been associated with mitochondrial dysfunction in nonpregnant adults, and HIV, additionally, to apoptosis. We determined whether mitochondrial toxicity and apoptosis are present in HIV-pregnant women and their newborns and could be the basis of adverse pregnancy outcome. Single-site, cross-sectional, controlled observational study without intervention. We studied mitochondrial and apoptotic parameters in mononuclear cells from maternal peripheral blood and infant cord blood at delivery in 27 HIV-infected and treated pregnant women, and 35 uninfected controls and their infants, to correlate clinical outcome with experimental findings: mitochondrial number (CS), mtDNA content (ND2/18SrRNA), mitochondrial protein synthesis (COX-II/V-DAC), mitochondrial function (enzymatic activities) and apoptotic rate (caspase-3/β-actin). Global adverse perinatal outcome, preterm births and small newborn for gestational age were significantly increased in HIV pregnancies [odds ratio (OR) 7.33, 5.77 and 9.71]. Mitochondrial number was unaltered. The remaining mitochondrial parameters were reduced in HIV mothers and their newborn; especially newborn mtDNA levels, maternal and fetal mitochondrial protein synthesis and maternal glycerol-3-phosphate + complex III function (38.6, 25.8, 13.6 and 31.2% reduced, respectively, P < 0.05). All materno-fetal mitochondrial parameters significantly correlated, except mtDNA content. Apoptosis was exclusively increased in infected pregnant women, but not in their newborn. However, adverse perinatal outcome did not correlate mitochondrial or apoptotic findings. Transplacental HAART toxicity may cause subclinical mitochondrial damage in HIV-pregnant women and their newborn. Trends to increased maternal apoptosis may be due to maternal-restricted HIV infection. However, we could not demonstrate mitochondrial or apoptotic implication in adverse perinatal outcome.

Background.Nucleoside reverse-transcriptase inhibitor (NRTI)-related mitochondrial toxicity has been suggested as a key factor in the induction of an