Autophagy is required for the homeostasis of cellular material and is proposed to be involved in many aspects of health. Defects in the autophagy pathway have been observed in neurodegenerative disorders; however, no genetically-inherited pathogenic mutations in any of the core autophagy-related (ATG) genes have been reported in human patients to date. We identified a homozygous missense mutation, changing a conserved amino acid, in ATG5 in two siblings with congenital ataxia, mental retardation, and developmental delay. The subjects' cells display a decrease in autophagy flux and defects in conjugation of ATG12 to ATG5. The homologous mutation in yeast demonstrates a 30-50% reduction of induced autophagy. Flies in which Atg5 is substituted with the mutant human ATG5 exhibit severe movement disorder, in contrast to flies expressing the wild-type human protein. Our results demonstrate the critical role of autophagy in preventing neurological diseases and maintaining neuronal health.DOI: http://dx.doi.org/10.7554/eLife.12245.001

The aim of this study was to investigate the degree to which genetic and environmental influences affect variation in adolescent optimism. Optimism (3 items and 6 items approach) and pessimism were assessed by the Life Orientation Test-Revised (LOT-R) in 5,187 adolescent twins and 999 of their non-twin siblings from the Netherlands Twin Register (NTR). Males reported significantly higher optimism scores than females, while females score higher on pessimism. Genetic structural equation modeling revealed that about one-third of the variance in optimism and pessimism was due to additive genetic effects, with the remaining variance being explained by non-shared environmental effects. A bivariate correlated factor model revealed two dimensions with a genetic correlation of −.57 (CI −.67, −.47), while the non-shared environmental correlation was estimated to be −.21 (CI −.25, −.16). Neither an effect of shared environment, non-additive genetic influences, nor quantitative sex differences was found for both dimensions. This result indicates that individual differences in adolescent optimism are mainly accounted for by non-shared environmental factors. These environmental factors do not contribute to the similarity of family members, but to differences between them. Familial resemblance in optimism and pessimism assessed in adolescents is fully accounted for by genetic overlap between family members.

Decomposing the structure of human cerebral function in its domains, such as affect regulation or cognition, forms the backbone of psychiatric diagnosis and treatment. Research continues to decipher the domains and hierarchical structure of cerebral function. So far, the findings strongly suggest two higher-order latent factors of general psychopathology (p factor) and general intelligence (g factor). Both general factors are functions of the same organ, covary, share risk factors as well as biomarkers, and benefit from the same treatments. However, to our knowledge, a model that connects both components of cerebral function within a higher-order latent factor and describes its potential biological underpinning is lacking. First, we suggest the general factor of cerebral function (c factor) as the shared variance of the measures of g and p in a bi-factor model. Second, we propose and provide evidence that mitochondrial bioenergetics (MB) is one core biological underpinning of c. Third, we describe how this c factor mito-bioenergetics (CMB) model may transform research and clinical practice by advancing knowledge of treatment effects, risk factors, biomarkers and clinical outcomes. Finally, we present a CMB model-based hypothesis stating that fatigue—as a phenotypical correlate of MB—directly loads on c.

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Major depressive disorder (MDD) causes enormous individual suffering and socioeconomic costs. Biochemical mechanisms leading to MDD are poorly understood and therapy success is not satisfactory. At present, there is evidence of low-grade inflammation, oxidative stress, and most interestingly, a disturbed energy metabolism in MDD and other mental health diseases. Mitochondria play a central part in energy production and stress signaling. Mitochondrial electron transport chain uses molecular oxygen (O2) as final electron acceptor during adenosine triphosphate production attributing a crucial role to an intact O2 supply. Adaptation to altered O2 availability by the highly conserved hypoxic response is essential for maintaining allostasis. Previous research confirmed the role of O2 metabolism in the pathophysiology of MDD. In this perspective article, we compile the evidence linking O2 transport, O2 homeostasis, and mitochondrial energy metabolism to MDD. Furthermore, we hypothesize that inflammation and oxidative stress-related alterations in O2 transport might lead to a hypoxic response, which explains changes in O2 homeostasis and energy metabolism in MDD. Our forthcoming studies will investigate the interplay between energy metabolism and O2 homeostasis in MDD that aim to improve the overall understanding of the pathophysiology of MDD and to guide medical and psychological diagnostics towards a holistic strategy.