The majority of axonal mitochondria in mammalian neuronslack mitochondrial DNA and do not produce ATP

A new study overturns a long-held assumption about how neurons power themselves, revealing a striking division of labor inside brain cells. Researchers studying cortical pyramidal neurons (CPNs), the long-distance relay cells that make up a large portion of the brain's cortex, found that the mitochondria sitting inside axons, the long wire-like extensions neurons use to send signals, are mostly non-functional in a critical way. Mitochondria are often called the cell's powerhouses because they generate ATP, the molecule cells use as fuel, through a process called oxidative phosphorylation, which requires mitochondrial DNA (mtDNA). But the new findings show that the majority of axonal mitochondria in CPNs actually lack mtDNA entirely, meaning their energy-producing machinery is largely switched off. Even more surprisingly, instead of making ATP, these axonal mitochondria appear to be consuming it, running a key molecular motor called ATP synthase in reverse just to keep themselves electrically stable.

The picture looks completely different on the other side of the same neuron. In dendrites, the branching extensions that receive incoming signals, mitochondria are large, fused together into networks, packed with mtDNA, and actively churning out ATP through oxidative phosphorylation. The researchers propose that axons instead rely on glycolysis, a simpler and older form of energy production that breaks down glucose directly in the cell's fluid, to meet their ATP needs. The study, which is a preprint and has not yet been peer reviewed, also offers four speculative explanations for why evolution might have favored this arrangement, including the idea that fully active mitochondria generate damaging byproducts and heat that could interfere with the delicate chemistry of synaptic signaling.