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New therapies to prevent the 'energy crisis' in neurons


Axonal energy deficits occur in chronic neurodegenerative diseases, but also after acute brain injury or in circulatory disorders (e.g., ischemia). Therefore, new therapeutic approaches to increase the production of energy carriers in our cells are considered key strategies to support neuronal survival and regeneration of the nervous system. Adenosine triphosphate (ATP) is produced in the 'power plants' of cells, the mitochondria, which are currently the subject of intensive research in many laboratories worldwide.


The transport of axonal mitochondria, their biogenesis and quality control are crucial for the maintenance of the neuronal mitochondrial pool. Unlike proliferating cells, which primarily use oxygen-independent glycolysis for ATP production, neurons rely primarily on oxidative phosphorylation (OXPHOS) to generate ATP in the presence of oxygen. Neurons are therefore particularly vulnerable to mitochondrial dysfunction and oxygen starvation.


Due to their often highly branched projections, nerve cells have a particularly high energy requirement in order to cope with the production and release of neurotransmitters. The mitochondria required for this must be transported into all of the terminal branches of the axon. Mitochondrial dysfunction is therefore first noticeable in highly branched neurons and represents an important pathological feature of neurodegenerative diseases.


Recent studies have uncovered those mechanisms that neurons use to maintain the quantity and integrity of axonal mitochondria and their bioenergetic capacity. In particular, experimental models of PD are used because in these, the highly branched axonal trees of midbrain neurons, which have particularly high energy demands, are affected first.


Propagation of our cellular power plants is a very laborious process. Since mitochondria cannot be generated de novo, mitochondrial biogenesis depends mainly on the incorporation of newly synthesized proteins and lipids into existing mitochondria, which are then cleaved. Mitochondria are composed of more than 1,000 proteins, most of which are encoded in the nucleus (only 13 are made by the mitochondrial DNA, or mtDNA).


In the neuronal cell body (perikaryon), mitochondria form an interconnected network, whereas in axons they are vesicular or short, tubular structures. Smaller mitochondria have a lower bioenergetic capacity. However, they exhibit higher mobility along axons and are especially found at axonal branch points and energy-intensive synapses.


Over half of the ATP required by neurons is consumed in axonal terminals. There, about one million ATP molecules are required to restore ion gradients and calcium levels. For example, 20,000 ATP molecules are necessary for each recycling process of synaptic glutamate vesicles.


Because of their low mobility in mature neurons, a mitochondrion in the neuronal perikaryon would take days to move from the cell body to the axonal terminals of a large neuron with a long axon. We must therefore assume that mitochondria also proliferate in axons. Indeed, there is now sufficient evidence of axonal mtDNA replication and mRNA translation of mitochondrial proteins.


Moreover, it has been known for some time that mitochondria can migrate along axonal microtubules and be arrested at sites of high energy demand. This ensures an adequate and stable supply of ATP in metabolically active regions. Thus, the transport and also the arrest of axonal mitochondria can be regulated to allow a neuron to respond to changing metabolic requirements during neuronal growth, regeneration, but also during high synaptic activity.


Prolonged mitochondrial dysfunction is a key problem because it leads to energy deficits and axonal degeneration. It also increases the risk of oxidative damage, as mitochondria are considered major sources of reactive oxygen species (ROS). Therefore, restoration of damaged mitochondria represents a critical step in maintaining axonal bioenergetics.


Free radicals can lead to defective structures of mitochondrial proteins, which are subsequently degraded by mitochondrial proteases at the inner membrane and in the matrix. Mitophagy represents another form of mitochondrial quality control. It is a special form of autophagy, as whole or fragmented mitochondria are enclosed by membranes and degraded.


As described in my book on neurodegeneration, a major mitophagy mechanism is activated via phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) and via the E3 ubiquitin ligase parkin (PARK2). Both are genetically associated with familial Parkinson's disease. Blocking mitophagy in parkin or pink1 mutants leads not only to an increase in axonal mitochondrial density, but also to an accumulation of damaged mitochondria in the cell body. This suggests that mitophagy occurs primarily in the neuronal perikaryon rather than axons.


To facilitate mitophagy in distal axons, axonal mitochondria are arrested by degradation of the protein MIRO1 that couples mitochondria to microtubule motor proteins and is regulated by the parkin-ubiquitination-proteasome pathway. Thus, when MIRO1 degradation is impaired, mitochondria are no longer arrested for mitophagy and accumulate.


It is interesting to note that in major neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and other syndromes, specific gene mutations impair mitochondrial transport, their anchoring, fission, or fusion, thus compromising bioenergetic metabolism and mitochondrial quality control.


New developments on therapeutic approaches are particularly concerned with mitochondrial metabolism and cell-to-cell transfer of mitochondria. This intercellular organelle transport can occur via extracellular vesicles or so-called tunnel nanotubes (TNTs), which transfer healthy mitochondria to recipient cells with energy deficits. In the brains of mice with transient focal cerebral ischemia, healthy mitochondria have already been released from glial cells (astrocytes) into the extracellular space and transferred into energetically stressed neurons, thus promoting neuronal survival.


In addition, a bioenergetic deficit can be compensated by the transfer of mitochondria from neural stem cells. In general, however, such mitochondrial transplantation can also be achieved directly by administering isolated mitochondria by intracerebral or intraarterial injection. This restores oxidative phosphorylation in ischemic animal models and mitochondrial integrity in defective CNS neurons. Although uptake of exogenous mitochondria via the cell surface (macropinocytosis) is suspected, the exact mechanisms regulating mitochondrial entry into recipient cells are still largely unknown.


A pharmacological approach to promote mitochondrial metabolism results from our knowledge of nicotinamide. NAD (nicotinamide adenine dinucleotide) is found in fruits, vegetables, meat, and milk and is an essential metabolic factor that is crucial for diverse cellular processes, e.g., in addition to energy metabolism, repair of damage to the genome. Elevated cellular NAD levels have been shown to extend lifespan and protect neurons from various forms of stress in animal studies. In a recently published placebo-controlled study of 30 Parkinson's patients, Charalampos Tzoulis of Haukeland University Hospital in Norway demonstrated that taking nicotinamide riboside increased NAD levels in the brain and thus its activity. Statistically significant improvements in Parkinson's symptoms could be demonstrated.


NAD is a crucial cofactor in various metabolic reactions related to energy metabolism (glycolysis, fatty acid oxidation, citric acid cycle). It also provides a co-substrate for the sirtuin family of deacylases (SIRTs), which regulate numerous mitochondrial processes such as oxidative phosphorylation, mitochondrial quality control, and their biogenesis. NAD is produced from the essential amino acid tryptophan or NAD precursor molecules and also reduces amyloid protein aggregation and cytotoxicity in animal models of Alzheimer's disease.


From the group of bioenergetic compounds that can cross the blood-brain barrier, creatine would be a potential therapeutic metabolite that has been successfully used in CNS injury rodent models. Creatine is converted to phosphocreatine (PCr) by creatine kinase. In hypoxia and ischemia models, creatine administration attenuates axonal ATP loss, thereby reducing axonal damage. However, creatine administration also ameliorates cortical damage caused by traumatic brain injury and promotes locomotor function in animal models of paraplegia. Unfortunately, the studies conducted to date in patients with neurodegenerative diseases have not been convincing. However, the future development of more effective bioenergetic preparations seems to be a promising therapeutic approach to remedy the neuronal energy crisis.


References:


Brakedal B, Dölle C, Riemer F, ..., Tzoulis C (2022) The NADPARK study: a randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease. Cell Metabolism 34:396


Burtscher J, Romani M, Bernardo G, Popa T, Ziviani E, Hummel FC, Sorrentino V, Millet GP (2022) Boosting mitochondrial health to counteract neurodegeneration. Progress in Neurobiology 215:102289


Cheng X-T, Huang N, Sheng Z-H (2022) Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration. Neuron 110:1899


Magalhães JD, Cardoso SM (2023) Mitochondrial signaling on innate immunity activation in Parkinson disease. Current Opinion in Neurobiology 78:102664.


Image credit: iStock/Sci-Monde

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