Mitochondrial dysfunction in autism

Mitochondrial dysfunction with defects in oxidative phosphorylation has been suspected in autism and several recent findings that show abnormalities in mitochondrial enzyme activities that support hypothesis. Postmortem examination of autistic brains revealed significantly elevated calcium levels in autistic brains compared to controls, followed by elevations of mitochondrial aspartate/glutamate carrier rates and mitochondrial metabolism and oxydation rates (18607376]. Disturbance of mitochondrial energy production in autism was confirmed by another recent study [19043581]. (also see Brain Development and Oxydative Stress). also see Brain Development and Oxidative Stress).

When compared to controls autistic patients show significantly lower carnitine levels, followed by elevated levels of lactate, aspartate aminotransferase, creatine kinase and significantly elevated levels of alanine and ammonia [16566887, 15739723, 15679182]. A pilot study investigating brain high energy phosphate and membrane phospholipid metabolism in individuals with autism found decreased levels of phosphocreatine and esterified ends (alpha ATP + alpha ADP + dinucleotides + diphosphosugars) compared to the controls. When the metabolite levels were compared with neuropsychologic and language test scores, a common pattern of correlations was observed across measures in the autistic group, wherein as test performance declined, levels of high energy phosphate compounds and of membrane building blocks decreased, and levels of membrane breakdown products increased. The authors concluded that the results of the study provided tentative evidence of alterations in brain energy and phospholipid metabolism in autism that correlate with the level of neuropsychologic and language deficits [8373914] (also see Membrane). This was further confirmed by another study finding the impairment of energy metabolism in autistic patients which could be correlated to the oxidative stress (19376103). Also see Oxidative Stress


Calcium homeostasis and mitochondria

One of the functions of mitochondria is to store free calcium. Release of this stored calcium back into the interior of the cell can initiate calcium spikes or waves. These events coordinate various processes in different types of cells, for example neurotransmitter release in nerve cells and release of hormones in endocrine cells. Excess calcium ions stored in mitochondria can inhibit oxidative phosphorylation. In the nerve cells this can causes an irreversible reduction in the energy status of nerve terminals, which can initiate pathophysiological processes in those cells.

Numerous findings have indicated a crucial role of calcium influx through L-type calcium channels in mitochondrial calcium overload and downstream mitochondrial and cellular dysfuctions. It has been shown that blockade of LTCC in the plasma membrane not only inhibits an increase in cellular calcium but also stabilizes mitochondrial membranes calcium homeostasis and generation of ROS by mitochondria [16760264, 11746731]. In one study inhibition of calcium inward current with verapamil protected against oxidative stress as well as morphological changes and dysfunction of mitochondria [16644187] (Oxidative_Stress). There are some indications that, simultanious to LTCC, N-methyl-D-aspartate (NMDA) receptors are also involved in oxidative stress, mitochondrial dysfunction, and ATP depletion mediated by calcium influx [12473387].

The involvement of LTCC in cellular and mitochondrial accumulation of calcium has been demonstrated in vitro in hypoxic renal tubular cells [15339981], and in bovine chromaffin cells [11500491], showing that these channels play an important role in regulating mitochondrial permeability transition, cytochrome c release, caspase activation, and ATP depletion-induced mitochondrial apoptosis. The reduced efficiency of handling of intracellular calcium loads in neurons may be an important factor contributing to the onset of neuronal damage during hypoxia and ischaemia [8012725]. Calcium influx through LTCC is involved in the ischemic damage in neonatal brain which manifests itself as a decrease in the energy state, with decreased levels of phosphocreatine and ATP, and an increases in lactate [88974726] (see Hypoxia/Ischemia).

At the same time deenergization of mitochondria affects the cellular calcium influx rate [10930575]. Several inherited human encephalomyopathies exhibit neurological symptoms, including autism-related symptoms, in association with specific mitochondrial mutations [7846043]. It can therefore be proposed that this inability to regulate calcium influx and homeostasis is one of the probable mechanisms behind increased neuronal vulnerability and subsequent development of autistic-like behavioural symptoms in human encephalomyopathies.