The potential role of mitochondria in pediatric traumatic brain injury

Mitochondria play a central role in cerebral energy metabolism, intracellular calcium homeostasis and reactive oxygen species generation and detoxification. Following traumatic brain injury (TBI), the degree of mitochondrial injury or dysfunction can be an important determinant of cell survival or death. Literature would suggest that brain mitochondria from the developing brain are very different from those from mature animals. Therefore, aspects of developmental differences in the mitochondrial response to TBI can make the immature brain more vulnerable to traumatic injury. This review will focus on four main areas of secondary injury after pediatric TBI, including excitotoxicity, oxidative stress, alterations in energy metabolism and cell death pathways. Specifically, we will describe what is known about developmental differences in mitochondrial function in these areas, in both the normal, physiologic state and the pathologic state after pediatric TBI. The ability to identify and target aspects of mitochondrial dysfunction could lead to novel neuroprotective therapies for infants and children after severe TBI.     

Brain metabolism and brain disease: Is metabolic deficiency the proximate cause of Alzheimer dementia?

The potential of impairments in oxidative/energy metabolism to cause diseases of the brain had been proposed even before the major pathways of oxidative/energy metabolism were described. Deficiencies associated with disease are known in all the pathways of oxidative/energy metabolism and are associated with some of the most common disorders of the nervous system, including Alzheimer's disease (AD) and Parkinson's disease. A common mechanism in these conditions appears to be a downward mitochondrial spiral, involving abnormalities in energy metabolism, calcium metabolism, and free radicals (reactive oxygen and nitrogen species). In AD, the spiral appears to interact with abnormalities in the metabolism of the Alzheimer amyloid precursor protein (APP) and its Abeta fragment. Several lines of evidence indicate that the mitochondrial spiral may be a proximate cause of the clinical disabilities in AD. Decreases in cerebral metabolic rate (CMR) characteristically occur in AD and in other dementias. Inducing decreases in CMR leads to clinical disabilities characteristically associated with AD and with analogous problems in experimental animals. Treatments directed toward normalizing CMR appear to help at least some patients. Further studies of this possibility and of treatments designed to ameliorate the mitochondrial spiral may prove useful for treating AD and perhaps some other dementing disorders.     

Affective disorders,antidepressant drugs and brain metabolism

There is increasing evidence that affective disorders are associated with dysfunction of neurotransmitter postsynaptic transduction pathways and that chronic treatment with clinically active drugs results in adaptive modification of these pathways. Despite the close dependence of signal transduction on adenosine triphosphate (ATP) availability, the changes in energy metabolism in affective disorders are largely unknown. This question has been indirectly dealt with through functional imaging studies (PET, SPECT, MRS). Despite some inconsistencies, PET and SPECT studies suggest low activity in cortical (especially frontal) regions in depressed patients, both unipolar and bipolar, and normal or increased activity in the manic pole. Preliminary MRS studies indicate some alterations in brain metabolism, with reduced creatine phosphate and ATP levels in the brain of patients with affective disorders. However, the involvement of the energy metabolism in affective disorders is still debated. We propose direct neurochemical investigations on mitochondrial functional parameters of energy transduction, such as the activities of (a) the enzymatic systems of oxidative metabolic cycle (Kreb's cycle); (b) the electron transfer chain; (c) oxidative phosphorylation, and (d) the enzyme activities of ATP-requiring ATPases. These processes should be studied in affective disorders and in animals treated with antidepressant drugs or lithium.     

Brain glucose metabolism: Role of Wnt signaling in the metabolic impairment in Alzheimer’s disease

The brain is an organ that has a high demand for glucose. In the brain, glucose is predominantly used in energy production, with almost 70% of the energy used by neurons. The importance of the energy requirement in neurons is clearly demonstrated by the fact that all neurodegenerative disorders exhibit a critical metabolic impairment that includes decreased glucose uptake/utilization and decreased mitochondrial activity, with a consequent diminution in ATP production. In fact, in Alzheimer’s disease, the measurement of the general metabolic rate of the brain has been reported to be an accurate tool for diagnosis. Additionally, the administration of metabolic activators such as insulin/glucagon-like peptide 1 can improve memory/learning performance. Despite the importance of energy metabolism in the brain, little is known about the cellular pathways involved in the regulation of this process. Several reports postulate a role for Wnt signaling as a general metabolic regulator. Thus, in the present review, we discuss the antecedents that support the relationship between Wnt signaling and energy metabolism in the Alzheimer’s disease.     

Energy metabolism in disorders of the nervous system

"Energy metabolism" is deranged in a wide variety of disorders of the nervous system. This term refers rather loosely to the pathways responsible for the utilization of the major substrates of brain. Primary disorders of energy metabolism are those in which the primary insult affects the cellular machinery required for energy metabolism. A typical example would be a defect in a gene coding for a mitochondrial protein. Biochemically, defects which appear to be hereditary and which lead to disease of the central nervous system have been described in each of the pathways of energy metabolism: glycogenolysis (the break-down of glycogen to glucose); glycolysis (the break down of glucose to pyruvate and lactate); the pyruvate dehydrogenase complex (which oxidizes pyruvate to enter the Krebs tricarboxylic acid cycle); the tricarboxylic acid cycle itself (which completes the oxidation of carbohydrates and other substrates to carbon dioxide); electron transport (which carries out their oxidation to water); the pentose phosphate pathway (an alternate pathway for glucose oxidation); and several "minor" mitochondrial pathways. Clinically, the spectrum of syndromes associated with primary disorders of energy metabolism is wide. Common manifestations include psychomotor retardation, with associated lactic acidosis and/or hypoglycemia. The laboratory abnormalities may be intermittent. Syndromes which have been culled out include congenital lactic acidosis, Leigh disease, intermittent ataxia, Kearns-Sayre-Shy syndrome (KSS), myoclonus epilepsy with ragged red fibers (MERRF), and mitochondrial myopathy-encephalopathy-lactic acidosis-stroke (MELAS). As with other families of inborn errors, both clinical and biochemical heterogeneity occur. Patients with apparently similar clinical syndromes can turn out to have different inborn errors, and patients with abnormalities of the same gene product can have clinically distinguishable syndromes. Secondary disorders are those in which the derangements of energy metabolism are presumably secondary to some other insult but may still be important for the cellular pathophysiology. These include the metabolic encephalopathies and probably a number of well-known neurodegenerative disorders. In the hereditary ataxias, abnormalities of mitochondrial markers are common but do not correlate consistently with the disorders as conventionally classified; a new classification into axonal ataxias, multiple system degenerations, and ataxic encephalopathies may be easier to relate to the pathophysiology.(ABSTRACT TRUNCATED AT 400 WORDS)     

Functional implications of hypothalamic neurogenesis in the adult mammalian brain

Adult neurogenesis represents a striking example of structural plasticity in the mature brain. Research on adult mammalian neurogenesis today focuses almost exclusively on two areas: the subgranular zone (SGZ) in the dentate gyrus of the hippocampus, and the subventricular zone (SVZ) of the lateral ventricles. Numerous studies, however, have also reported adult neurogenesis in the hypothalamus, a brain structure that serves as a central homeostatic regulator of numerous physiological and behavioral functions, such as feeding, metabolism, body temperature, thirst, fatigue, aggression, sleep, circadian rhythms, and sexual behavior. Recent studies on hypothalamic neurogenesis have identified a progenitor population within a dedicated hypothalamic neurogenic zone. Furthermore, adult born hypothalamic neurons appear to play a role in the regulation of metabolism, weight, and energy balance. It remains to be seen what other functional roles adult hypothalamic neurogenesis may play. This review summarizes studies on the identification and characterization of neural stem/progenitor cells in the mammalian hypothalamus, in what contexts these stem/progenitor cells engage in neurogenesis, and potential functions of postnatally generated hypothalamic neurons.     

Mitochondrial mechanisms of cell death and neuroprotection in pediatric ischemic and traumatic brain injury

There are several forms of acute pediatric brain injury, including neonatal asphyxia, pediatric cardiac arrest with global ischemia, and head trauma, that result in devastating, lifelong neurologic impairment. The only clinical intervention that appears neuroprotective is hypothermia initiated soon after the initial injury. Evidence indicates that oxidative stress, mitochondrial dysfunction, and impaired cerebral energy metabolism contribute to the brain cell death that is responsible for much of the poor neurologic outcome from these events. Recent results obtained from both in vitro and animal models of neuronal death in the immature brain point toward several molecular mechanisms that are either induced or promoted by oxidative modification of macromolecules, including consumption of cytosolic and mitochondrial NAD⁺ by poly-ADP ribose polymerase, opening of the mitochondrial inner membrane permeability transition pore, and inactivation of key, rate-limiting metabolic enzymes, e.g., the pyruvate dehydrogenase complex. In addition, the relative abundance of pro-apoptotic proteins in immature brains and neurons, and particularly within their mitochondria, predisposes these cells to the intrinsic, mitochondrial pathway of apoptosis, mediated by Bax- or Bak-triggered release of proteins into the cytosol through the mitochondrial outer membrane. Based on these pathways of cell dysfunction and death, several approaches toward neuroprotection are being investigated that show promise toward clinical translation. These strategies include minimizing oxidative stress by avoiding unnecessary hyperoxia, promoting aerobic energy metabolism by repletion of NAD⁺ and by providing alternative oxidative fuels, e.g., ketone bodies, directly interfering with apoptotic pathways at the mitochondrial level, and pharmacologic induction of antioxidant and anti-inflammatory gene expression.     

Mitochondrial dysfunction and nicotinamide dinucleotide catabolism as mechanisms of cell death and promising targets for neuroprotection

Both acute and chronic neurodegenerative diseases are frequently associated with mitochondrial dysfunction as an essential component of mechanisms leading to brain damage. Although loss of mitochondrial functions resulting from prolonged activation of the mitochondrial permeability transition (MPT) pore has been shown to play a significant role in perturbation of cellular bioenergetics and in cell death, the detailed mechanisms are still elusive. Enzymatic reactions linked to glycolysis, the tricarboxylic acid cycle, and mitochondrial respiration are dependent on the reduced or oxidized form of nicotinamide dinucleotide [NAD(H)] as a cofactor. Loss of mitochondrial NAD(+) resulting from MPT pore opening, although transient, allows detrimental depletion of mitochondrial and cellular NAD(+) pools by activated NAD(+) glycohydrolases. Poly(ADP-ribose) polymerase (PARP) is considered to be a major NAD(+) degrading enzyme, particularly under conditions of extensive DNA damage. We propose that CD38, a main cellular NAD(+) level regulator, can significantly contribute to NAD(+) catabolism. We discuss NAD(+) catabolic and NAD(+) synthesis pathways and their role in different strategies to prevent cellular NAD(+) degradation in brain, particularly following an ischemic insult. These therapeutic approaches are based on utilizing endogenous intermediates of NAD(+) metabolism that feed into the NAD(+) salvage pathway and also inhibit CD38 activity.     

6-Hydroxydopamine induces different mitochondrial bioenergetics response in brain regions of rat

Mitochondrial dysfunction has been demonstrated to have a central role in Parkinson Disease (PD) pathophysiology. Some studies have indicated that PD causes an impairment in mitochondrial bioenergetics; however, the effects of PD on brain-region specific bioenergetics was never investigated before. This study aimed to evaluate mitochondrial bioenergetics in different rat brain structures in an in vitro model of PD using 6-OHDA. Rat brain slices of hippocampus, striatum, and cortex were exposed to 6-OHDA (100 μM) for 1 h and mitochondrial bioenergetic parameters, peroxide production, lactate dehydrogenase (LDH) and citrate synthase (CS) activities were analyzed. Hippocampus slices exposed to 6-OHDA presented increased peroxide production but, no mitochondrial adaptive response against 6-OHDA damage. Cortex slices exposed to 6-OHDA presented increased oxygen flux related to oxidative phosphorylation and energetic pathways exchange demonstrated by the increase in LDH activity, suggesting a mitochondrial compensatory response. Striatum slices exposed to 6-OHDA presented a decrease of oxidative phosphorylation and decrease of oxygen flux related to ATP-synthase indicating an impairment in the respiratory chain. The co-incubation of 6-OHDA with n-acetylcysteine (NAC) abolished the effects of 6-OHDA on mitochondrial function in all brain regions tested, indicating that the increased reactive oxygen species (ROS) production is responsible for the alterations observed in mitochondrial bioenergetics. The present results indicate a brain-region specific response against 6-OHDA, providing new insights into brain mitochondrial bioenergetic function in PD. These findings may contribute to the development of future therapies with a target on energy metabolism.     

Mitochondrial detachment of hexokinase 1 in mood and psychotic disorders: implications for brain energy metabolism and neurotrophic signaling

The pathophysiology of mood and psychotic disorders, including unipolar depression (UPD), bipolar disorder (BPD) and schizophrenia (SCHZ), is largely unknown. Numerous studies, from molecular to neuroimaging, indicate that some individuals with these disorders have impaired brain energy metabolism evidenced by abnormal glucose metabolism and mitochondrial dysfunction. However, underlying mechanisms are unclear. A critical feature of brain energy metabolism is attachment to the outer mitochondrial membrane (OMM) of hexokinase 1 (HK1), an initial and rate-limiting enzyme of glycolysis. HK1 attachment to the OMM greatly enhances HK1 enzyme activity and couples cytosolic glycolysis to mitochondrial oxidative phosphorylation, through which the cell produces most of its adenosine triphosphate (ATP). HK1 mitochondrial attachment is also important to the survival of neurons and other cells through prevention of apoptosis and oxidative damage. Here we show, for the first time, a decrease in HK1 attachment to the OMM in postmortem parietal cortex brain tissue of individuals with UPD, BPD and SCHZ compared to tissue from controls without psychiatric illness. Furthermore, we show that HK1 mitochondrial detachment is associated with increased activity of the polyol pathway, an alternative, anaerobic pathway of glucose metabolism. These findings were observed in samples from both medicated and medication-free individuals. We propose that HK1 mitochondrial detachment could be linked to these disorders through impaired energy metabolism, increased vulnerability to oxidative stress, and impaired brain growth and development.     

Neurogenesis in the adult ischemic brain: generation, migration, survival, and restorative therapy.

This article reviews current data on the induction of neurogenesis after stroke in the adult brain. The discussion of neurogenesis is divided into production, migration, and survival of these newly formed cells. For production, the subpopulations and the types of cell division are presented. Discussion of cell migration entails presenting data on both the pathways as well as the molecular targeting of newly formed neural progenitor cells to sites of injury. The role of the vascular and the astrocytic microenvironment in promoting the survival and integration of progenitor cells is also presented. Cell-based and pharmacological therapies designed to restore neurological function that promote neurogenesis are described. These therapies also induce angiogenesis and astrocytic changes that brain tissue, which prime the ischemic brain to foster the survival of the newly formed progenitor cells. Signaling pathways that regulate neurogenesis and angiogenesis are also addressed. This review summarizes recent data on neurogenesis and provides insight into the potential for restorative treatments of stroke.     

Hypothalamic control of seasonal changes in food intake and body weight

Seasonal cycles of fattening and body weight reflecting changes in both food intake and energy expenditure are a core aspect of the biology of mammals that have evolved in temperate and arctic latitudes. Identifying the neuroendocrine mechanisms that underlie these cycles has provided new insights into the hypothalamic control of appetite and fuel oxidation. Surprisingly, seasonal cycles do not result from changes in the leptin-responsive and homeostatic pathways located in the mediobasal and lateral hypothalamus that regulate meal timing and compensatory responses to starvation or caloric restriction. Rather, they result from changes in tanycyte function, which locally regulates transport and metabolism of thyroid hormone and retinoic acid. These signals are crucial for the initial development of the brain, so it is hypothesized that seasonal neuroendocrine cycles reflect developmental mechanisms in the adult hypothalamus, manifest as changes in neurogenesis and plasticity of connections.     

Adult hippocampal neurogenesis as target for the treatment of depression

The dentate gyrus (DG) is one of only two brain structures known to retain the ability to produce new neurons in adulthood. The functional significance of adult neurogenesis in the DG is not yet well understood, but recent evidence has implicated adult neurogenesis in the etiology and treatment of depression. Elevated stress hormone levels, which are present in some depressed patients and can precipitate the onset of depression, reduce neurogenesis in animal models. Conversely, virtually all antidepressant treatments studied to date, including drugs of various classes, electroconvulsive therapy, and behavioral treatments, increase neurogenesis in the DG. We critically review this literature linking DG neurogenesis with depression, looking to both animal and human studies. We conclude that a reduction in neurogenesis by itself is not likely to produce depression. However, at least some therapeutic effects of antidepressant treatments appear to be neurogenesis-dependent. We review the cellular pathways through which antidepressant drugs boost neurogenesis and present several hypotheses about how DG neurogenesis may be instrumental in the therapeutic effects of these drugs.     

Obesity-associated deterioration of the hippocampus is partially restored after weight loss

ObjectiveObesity is a multidimensional condition that is treatable by the restoration of a lean phenotype; however, some obesity-related outcomes may persist after weight normalization. Among the organs of the human body, the brain possesses a relatively low regenerative capacity and could retain perturbations established as a result of developmental obesity. Calorie restriction (CR) or a restricted ketogenic diet (KD) are successfully used as weight loss approaches, but their impact on obesity-related effects in the brain have not been previously evaluated.MethodsWe performed a series of experiments in a rat model of developmental obesity induced by a 12-week cafeteria diet, followed by CR to implement weight loss. First, we assessed the impact of obesity on neurogenesis (BrdU incorporation into the hippocampus), cognitive function (water maze), and concomitant changes in hippocampal protein expression (GC/MS-MS, western blot). Next, we repeated these experiments in a rat model of weight loss induced by CR. We also measured mitochondrial enzyme activity in rats after weight loss during the fed or fasting state. This study was extended by additional experiments with restricted KD used as a weight loss approach in order to compare the efficacy of two different nutritional interventions used in the treatment of obesity on hippocampal functions. By using a modified version of the water maze we evaluated cognitive abilities in rats subjected to weight loss by CR or a restricted KD.ResultsIn this study, obesity affected metabolic processes, upregulated hippocampal NF-κB, and induced proteomic differences which were associated with impaired cognition and neurogenesis. Weight loss improved neurogenesis and enhanced cognition. While the expression pattern of some proteins persisted after weight loss, most of the changes appeared de novo revealing metabolic adjustment by overactivation of citrate synthase and downregulation of ATP synthase. As a consequence of fasting, the activity of these enzymes indicated hippocampal adaptation to negative energy balance during the weight loss phase of CR. Moreover, the effects on cognitive abilities measured after weight loss were negatively correlated with the animal weight measured at the final stage of weight gain. This was alleviated by KD, which improved cognition when used as a weight loss approach.ConclusionsThe study shows that cognition and mitochondrial metabolism in the hippocampus are affected by CR- or KD-induced weight loss.     

Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-lll)

We have recently demonstrated in a rat model that traumatic brain injury induces perturbation of cellular calcium homeostasis with an overload of cytosolic calcium and excessive calcium adsorbed on the mitochondrial membrane, consequently the mitochondrial respiratory chain-linked oxidative phosphorylation. was impaired. We report the effect of a selective N-type calcium channel blocker, SNX-111 on mitochondrial dysfunction induced by a controlled cortical impact. Intravenous administration of SNX-111 at varying times post injury was made. The concentration titration profile revealed SNX-111 at 4 mg kg ^-1 to be optimal, and the time window to be administration at 4 h post-injury, in line with that reported on the effect of SNX-l11 in experimental stroke. Under optimal conditions, SNX-111 significantly improved the mitochondrial respiratory chain-linked functions, such as the electron transfer activities with both succinate and NAO-linked substrates, and the accompanied energy coupling capacities measured as respiratory control indices (RCI) and ATP synthesis (PIO ratio), and the energy linked Ca²⁺ transport. In order to assess the applicability of these data to the clinical setting, we have initiated studies with brain tissue which has to be resected during surgical treatment. Five patients suffered from brain trauma, o'!e from intrac;ranial hypertension due to stroke (noninfarcted tissue was taken), and one from epilepsy. Our data revealed that brain mitochondria derived from the patient with intracranial hypertension and the patient with epilepsy were tightly coupled with good respiratory rates with glutamate and malate as substrates, and high PIO ratios. The rates of respiration and ATP synthesis were severely impaired in the brain mitochondria isolated from traumatized patients. These results indicate that investigation of brain mitochondrial functions can be used as a measure for trauma-induced impairment of brain energy metabolism. The time window for the effect of SNX-lll in mitochondrial function and the (preliminary) similarity between mitochondrial dysfunction in experimental animals and humans make the drug appear to be .well suited for clinical trials in severe head injury. [Neural Res 1997; 19: 334–339]     

Practical issues in stem cell therapy for Alzheimer's disease

We have demonstrated that aged animals show significant improvements in cognitive function and neurogenesis after brain transplantation of human neural stem cells or of human adult mesenchymal stem cells that have been dedifferentiated by transfection of the embryonic stem cell gene. We have also demonstrated that peripheral administration of a pyrimidine derivative increased cognition, endogenous brain stem cell proliferation and neurogenesis. These results indicate a bright future for stem cell therapies in Alzheimer's disease (AD). Before this is realized, however, we need to consider the affect of AD pathology on stem cell biology to establish an effective stem cell therapy for this disease. Although amyloid-beta (Abeta) deposition is a hallmark of AD, an absence of a phenotype in the beta-amyloid precursor protein (APP) knockout mouse, might lead one to underestimate the potential physiological functions of APP and suggest that it is unessential or can be compensated for. We have found, however, that APP is needed for differentiation of neural stem cells (NSCs) in vitro, and that NSCs transplanted into a APP-knockout mouse did not migrate or differentiate -- indicating that APP plays an important role in differentiation or migration process of NSCs in the brain. Then again, treatment with high a concentration of APP or its over-expression increased glial differentiation of NSCs. Human NSCs transplanted into APP-transgenic mouse brain exhibited less neurogenesis and active gliosis around the plaque like formations. Treatment of such animals with the compound, (+)-phenserine, that is known to reduce APP protein levels, increased neurogenesis and suppressed gliosis. These results suggest APP levels can regulate NSC biology in the adult brain, that altered APP metabolism in Down syndrome or AD may have implications for the pathophysiology of these diseases, and that a combination of stem cell therapy and regulation of APP levels could provide a treatment strategy for these disorders.     

Sex differences and gonadal hormone regulation of brain cardiolipin,a key mitochondrial phospholipid

Cardiolipin (CL) is a phospholipid that is almost exclusively located in the inner mitochondrial membrane of eukaryotic cells. As a result of its unique structure and distribution, CL establishes non‐covalent bonds with a long list of proteins involved in ATP production, mitochondria biogenesis, mitophagy and apoptosis. Thus, the amount of CL, as well as its fatty acid composition and location, strongly impacts upon mitochondrial‐dependent functions and therefore the metabolic homeostasis of different tissues. The brain is particularly sensitive to mitochondrial dysfunction as a result of its high metabolic demand. Several mitochondrial related‐neurodegenerative disorders, as well as physiological ageing, show altered CL metabolism. Furthermore, mice lacking enzymes involved in CL synthesis show cognitive impairments. CL content and metabolism are regulated by gonadal hormones in the developing and adult brain. In neuronal cultures, oestradiol increases CL content, whereas adult ovariectomy decreases CL content and alters CL metabolism in the hippocampal mitochondria. Transient sex differences in brain CL metabolism have been detected during development. At birth, brain CL has a higher proportion of unsaturated fatty acids in the brain of male mice than in the brain of females. In addition, the expression of enzymes involved in CL de novo and recycling synthetic pathways is higher in males. Most of these sex differences are abolished by the neonatal androgenisation of females, suggesting a role for testosterone in the generation of sex differences in brain CL. The regulation of brain CL by gonadal hormones may be linked to their homeostatic and protective actions in neural cells, as well as the manifestation of sex differences in neurodegenerative disorders.     

When neurogenesis encounters aging and disease

In this review, we consider the evidence that a reduction in neurogenesis underlies aging-related cognitive deficits and impairments in disorders such as Alzheimer's disease (AD). The molecular and cellular alterations associated with impaired neurogenesis in the aging brain are discussed. Dysfunction of presenilin-1, misprocessing of amyloid precursor protein and toxic effects of hyperphosphorylated tau and β-amyloid probably contribute to impaired neurogenesis in AD. Because factors such as exercise, environmental enrichment and dietary energy restriction enhance neurogenesis, and protect against age-related cognitive decline and AD, knowledge of the underlying neurogenic signaling pathways could lead to novel therapeutic strategies for preserving brain function. In addition, manipulation of endogenous neural stem cells and stem cell transplantation, as stand-alone or adjunct treatments, seems promising.     

Inflammation, mitochondria, and the inhibition of adult neurogenesis

The process of neurogenesis continues throughout life, with thousands of new neurons generated every day in the mammalian brain. Impairment of hippocampal neurogenesis has been suggested to be involved in neurodegenerative conditions, including the cognitive decline associated with aging, Alzheimer's disease, Parkinson's disease, and ionizing radiation. These neurodegenerative conditions are all characterized by proinflammatory changes and increased numbers of activated microglia. Activated microglia produce a variety of proinflammatory factors, including interleukin-6, tumor necrosis factor-α, reactive oxygen species, and nitric oxide, all of which are antineurogenic. These same factors have also been shown to suppress mitochondrial function, but the role of mitochondria in neurogenesis remains barely investigated. This brief review summarizes the findings of several studies that support a role for mitochondrial impairment as part of the mechanism of the reduction of neurogenesis associated with inflammation.