Mitochondria, the organelles responsible for cellular energy production and metabolism, constantly get recycled. Through a process known as autophagy ("self-eating"), cells literally digest their damaged or aging mitochondria, clearing the way for healthy replacements.
The scientists showed that two existing classes of drugs counter the defect: the epilepsy drug carbamazepine, and drugs known as mTOR inhibitors. When treated, the dysfunctional neurons were able to clear damaged mitochondria and replenish healthy mitochondria, restoring a normal turnover.
Defects in mitophagy, or autophagy of mitochondria, have already been implicated in a number of neurologic disorders such as Parkinson's disease and Alzheimer's disease. Mitochondria have also been studied in autism for years, but the findings have been largely anecdotal and inconclusive, in part because the autism population is diverse and hard to define.
They studied both rat neurons and patient-derived neurons (created from induced pluripotent stem cells) affected by TSC and used live-cell imaging to examine the distribution and dynamics of mitochondria. They found that the TSC neurons as a whole had more mitochondria, and in particular more fragmented and dysfunctional mitochondria.
Then they examined the neurons' axons, the projections that send messages to other cells. Mitochondria play a critical role in axons, and are found in high numbers at presynaptic sites—the tips of axons that form synapses or junctions with other neurons and release neurotransmitters. But the axons of both rat neurons and neurons from TSC patients were depleted of mitochondria.
Diving deeper, they found that while mitophagy was increased in the body of the cell, it was reduced in the axons. Although proteins involved in the early steps of mitophagy increased in the axons, autophagosomes and lysosomes—the organelles that do the digesting—failed to appear around the damaged mitochondria. Instead, the mitochondria were being shuttled out of the axons, back to the body of the cell, without being replaced.
The researchers were able to restore normal mitophagy and replenish functioning mitochondria—in both neurons in a dish and in live mice—in several ways:
by reintroducing a healthy copy of the gene mutated in TSC
by adding rapamycin, an mTOR inhibitor that has shown to improve TSC in animal models and that is currently in clinical trials
with carbamazepine, a common anti-seizure medication, that enhances autophagy through a different mechanism of action than mTOR inhibitors.
Most notably, mitochondria were replenished at presynaptic sites, where their presence is most critical.
The findings shed intriguing light on what is already known about TSC and autism. Growing evidence, including from previous studies that autism, intellectual disability and seizures in many patients with TSC may result, at least in part, from synaptic dysfunction. Autism itself is increasingly seen as a disorder of synapses—and this study hints at one possible way synapses might go awry.