Maintaining mitochondria in neurons: A new lens for neurodegenerative disorders

cartoon of mitochondria being transported in neurons - part of mitostasis
In some neurons, mitochondria must travel several feet along an axon. (Elena Hartley illustration)

Tom Schwarz, PhD, is a neuroscientist at Boston Children’s Hospital’s F.M. Kirby Neurobiology Center, focusing on the cell biology of neurons. Tess Joosse is a biology major at Oberlin College. This article is condensed from a recent review article by Schwarz and Thomas Misgeld (Technical University of Munich).

Like all cells, the neurons of our nervous system depend on mitochondria to generate energy. Mitochondria need constant rejuvenation and turnover, and that’s especially true in neurons because of their high energy needs for signaling and “firing.” Mitochondria are especially abundant at presynaptic sites — the tips of axons that form synapses or junctions with other neurons and release neurotransmitters.

But the process of maintaining mitochondrial number and quality, known as mitostasis, also poses particular challenges in neurons. Increasingly, mitostasis is providing a helpful lens for understanding neurodegenerative disorders. Problems with mitostasis are implicated in Parkinson’s disease, Alzheimer’s disease, ALS, autism, stroke, multiple sclerosis, hypoxia and more.

The complexities of neurons

The first challenge stems from neurons’ complex architecture: a centralized body, or soma, where the genes reside and proteins are made; an “arbor” of branching, tree-like dendrites; and a long axon, ending in many arms of its own to transmit signals to other cells. Neurons can extend in many directions and branch off in irregular, changing paths. Some single axons in the human body can extend to a length of one meter. Others, including the neurons that are most vulnerable in Parkinson’s disease, are so highly branched that their branches add up to several meters.

These geometrical features raise several conundrums: where to make mitochondria, how to move them far distances, how to maintain their protein composition and structural integrity and how to keep up with the energy demands of a dynamic, unpredictable neuron.

Maintaining supply lines

Neurons get mitochondria in two ways: They can be synthesized in the soma and transported out to the axon and dendrites, or they can be made right where they’re needed, with the cell shuttling the necessary mitochondrial mRNA and ribosomal protein-synthesis machinery out to its extremities. Neurons also can obtain mitochondria from other cells through a process called organelle transfer, via small tubules and vesicles that move between cells.

neuron schematic: the challenge of mitostasis
In this mouse motor neuron, drawn approximately to scale, a small soma (A) with a limited pool of mitochondria has to supply a vast axonal arbor, as well as compartments like paranodes (B) and presynaptic terminals (C). (Used with permission of Neuron)

Once manufactured, neuronal mitochondria are frequently on the move, in more complex ways than in other kinds of cells. A neuron may have different ratios of moving versus stationary mitochondria over time and in different locations, depending on cell activities. Some mitochondria move in two directions; some fuse with each other or split during their travels.

Disease can result when genetic mutations disrupt factors that control the direction, timing and distances of movement of mitochondria — or the raw materials for making them. These factors are still largely unexplored.

Taking out the trash

Maintenance of a healthy mitochondrial population also requires the frequent clearance of damaged proteins. Proteins must be degraded, sequestered in lysosomes, digested and replaced, while mitochondria themselves are recycled through a digestive process called mitophagy. Mitochondria may return to the soma for degradation or get broken down on site, depending on the cell’s needs.

Disease can result when the cell’s pathways for recognizing the need for clearance, as well as clearance itself, are disrupted.

Mitochondrial maintenance and disease

A variety of neurologic disorders are known or thought to be associated with disruption of genes involved in mitostasis. Parkinson’s disease is the most common example. Some forms of familial Parkinson’s are due to mutations in PINK1 and Parkin that alter mitochondrial clearance. In other forms, studies show slowed degradation of a protein called Miro, leaving neurons unable to keep mitochondrial movement in check.

Tuberous sclerosis complex, a genetic syndrome associated with autism, also seems to cause problems with getting rid of or replacing damaged mitochondria. Mutations disrupting mitochondrial fusion and fission (splitting apart) can cause the degeneration of motor and sensory axons known as Charcot-Marie-Tooth disease type 2A, as well as autosomal-dominant optic atrophy, a disease of progressive blindness. In multiple sclerosis, mitochondrial damage is suspected to be a cause of axonal damage, possibly influenced by neuroinflammation.

Still other diseases are thought to result from failed regeneration of neurons that simply lack enough mitochondria to sustain growth. Mitochondria are also vulnerable to genetic mutations that disrupt the “motors” and tubules that carry them (and other organelles) around the cell.

Mind your mitostasis

If we stop breathing, we will quickly black out. That’s because our neurons depend so critically on the oxygen required for mitochondria. Considering how crucial mitochondria are to neuronal survival and the challenges that neurons face in supplying and maintaining millions of mitochondria in each cell, it isn’t surprising that mitochondria have moved to center stage in neurodegeneration and regeneration research.

Academic and biotech labs alike have developed a keen interest in understanding the cellular pathways that are active in the synthesis, deployment and clearance of mitochondria. The hope is that improving the health of mitochondria in the nervous system will improve the ability of neurons to survive. If new therapies can be developed based on mitochondrial health, they may keep us healthier too.

Read more in the full review article in Neuron.