Mitochondria impact brain function and cognition.

A revolution in our understanding of brain development, adult brain function, senescence, and disease has emerged from the recognition of structural and functional plasticity within the mammalian brain (1). For example, the role of brain-derived neurotrophic factor (BDNF) and other hormonal factors that mediate neurogenesis, as well as synaptic and dendritic plasticity in psychiatric disorders (2), has revealed unforeseen neuronal regulatory mechanisms. These build on a growing dynamic conception of brain architecture that complements the understanding of synaptic transmission. This, we are also discovering, is a plastic event altered by both structural and functional remodeling of the synapse. However, little is known about the role of mitochondria in regulating synaptic transmission, and less yet about their implications for cognitive function and memory decline in the aging brain (3). The study by Hara et al. (4) in PNAS synergizes with recent discoveries, revealing a key role of mitochondria regulating synaptic transmission, brain function, and cognition in aging. Mitochondria populate the cytoplasm of mammalian cells, including neurons, which rely on mitochondrial energy production for survival. These organelles contain their own genome—the mitochondrial DNA (mtDNA)— which encodes essential subunits of the respiratory chain where electrons are combined with oxygen to enable the flow of energy through mitochondria. Energized mitochondria can then synthesize ATP that fuels energy-dependent intracellular reactions (such as endocytosis, ion transport, and neurotransmitter biosynthesis) and sustain other critical mitochondrial functions [Ca handling, reactive oxygen species (ROS) production, and others], contributing to intracellular signaling (5). Equally important is the relatively recent discovery that mitochondria dynamically undergo shape changes through regulated processes of fusion and fission (making longer or shorter organelles, respectively) and actively traffic between cell compartments such as the soma, axon, and presynaptic boutons (6). Extracellular signals are known to directly affect mitochondria. For example, both glucocorticoid and estrogen receptors translocate into mitochondria and regulate Ca reuptake and ROS production (7, 8). Mitochondria also respond acutely to the metabolic environment by undergoing morphological and functional changes that may influence the cellular aging process (9). Interestingly, although mitochondrial dysfunction resulting from mtDNA mutations often cause severe multisystemic disease, the brain appears most vulnerable to mitochondrial defects, suggesting that neurons are particularly sensitive to bioenergetic fluctuations, and consequently, that mitochondria regulate fundamental aspects of brain function. In PNAS, Hara et al. reach across levels of knowledge to demonstrate a relationship between mitochondrial shape and age-related cognitive function. By performing 3D electron microscopy reconstructions of the brain area associated with working memory (dorsolateral prefrontal cortex) in monkeys, the authors characterized mitochondrial morphology at a high level of resolution within presynaptic boutons. In young monkeys, all mitochondria had normal morphology ranging from spheroid to elongated tubule. In contrast, presynaptic boutons in brains of older monkeys contained a significant number of donut-shaped (i.e., toroid) mitochondria (Fig. 1). Donut mitochondria are a hallmark of mitochondrial stress, inducible in controlled conditions (in vitro) by respiratory chain poisons and involving oxidative stress