Major depressive disorder (MDD) is the number one cause of disability worldwide and is comorbid with many chronic diseases, including obesity/metabolic syndrome (MetS). Women have twice as much risk for MDD and comorbidity with obesity/MetS as men, although pathways for understanding this association remain unclear. On the basis of clinical and preclinical studies, we argue that prenatal maternal stress (ie, excess glucocorticoid expression and associated immune responses) that occurs during the sexual differentiation of the fetal brain has sex-dependent effects on brain development within highly sexually dimorphic regions that regulate mood, stress, metabolic function, the autonomic nervous system, and the vasculature. Furthermore, these effects have lifelong consequences for shared sex-dependent risk of MDD and obesity/MetS. Thus, we propose that there are shared biologic substrates at the anatomical, molecular, and/or genetic levels that produce the comorbid risk for MDD-MetS through sex-dependent fetal origins.

Mutations in mitochondrial DNA polymerase (pol γ) cause several progressive human diseases including Parkinson's disease, Alper's syndrome, and progressive external ophthalmoplegia. At the cellular level, disruption of pol γ leads to depletion of mtDNA, disrupts the mitochondrial respiratory chain, and increases susceptibility to oxidative stress. Although recent studies have intensified focus on the role of mtDNA in neuronal diseases, the changes that take place in mitochondrial biogenesis and mitochondrial axonal transport when mtDNA replication is disrupted are unknown. Using high-speed confocal microscopy, electron microscopy and biochemical approaches, we report that mutations in pol γ deplete mtDNA levels and lead to an increase in mitochondrial density in Drosophila proximal nerves and muscles, without a noticeable increase in mitochondrial fragmentation. Furthermore, there is a rise in flux of bidirectional mitochondrial axonal transport, albeit with slower kinesin-based anterograde transport. In contrast, flux of synaptic vesicle precursors was modestly decreased in pol γ−α mutants. Our data indicate that disruption of mtDNA replication does not hinder mitochondrial biogenesis, increases mitochondrial axonal transport, and raises the question of whether high levels of circulating mtDNA-deficient mitochondria are beneficial or deleterious in mtDNA diseases.

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