Abstract
Neurons rely mostly on mitochondria for the production of ATP and Ca2+ homeostasis. As sub-compartmentalized cells, they have different pools of mitochondria in each compartment that are maintained by a constant mitochondrial turnover. It is assumed that most mitochondria are generated in the cell body and then travel to the synapse to exert their functions. Once damaged, mitochondria have to travel back to the cell body for degradation. However, in long cells, like motor neurons, this constant travel back and forth is not an energetically favourable process, thus mitochondrial biogenesis must also occur at the periphery. Ca2+ and ATP levels are the main triggers for mitochondrial biogenesis in the cell body, in a mechanism dependent on the Peroxisome-proliferator-activated γ co-activator-1α-nuclear respiration factors 1 and 2-mitochondrial transcription factor A (PGC-1α-NRF-1/2-TFAM) pathway. However, even though of extreme importance, very little is known about the mechanisms promoting mitochondrial biogenesis away from the cell body. In this review, we bring forward the evoked mechanisms that are at play for mitochondrial biogenesis in the cell body and periphery. Moreover, we postulate that mitochondrial biogenesis may vary locally within the same neuron, and we build upon the hypotheses that, in the periphery, local protein synthesis is responsible for giving all the machinery required for mitochondria to replicate themselves.
Highlights
Mitochondria are two-membrane organelles that contain their own DNA and can replicate independently of the host cell
For each disease a specific mechanism has been hypothesized to explain how mitochondrial malfunction leads to neuronal loss
Defects in mitochondrial biogenesis are characteristic of most neurodegenerative diseases, suggesting that the inability to replicate correctly is the common denominator leading to defective mitochondria
Summary
Mitochondria are two-membrane organelles that contain their own DNA and can replicate independently of the host cell. NRF-1 and NRF-2 act downstream of PGC-1α, regulating genes involved in OxPhos, and TFAM, resulting in increased mitochondrial respiration and mtDNA replication/transcription. CAMP-PKA-CREB pathway modulated PGC-1α, leading to the activation of NRF-1/2 and TFAM, promoting mitochondrial biogenesis (Figure 1). Ca2+ stimulates CaMK, which in turn phosphorylates p38MAPK, leading to the activation and expression of PGC-1α, resulting in increased mitochondrial biogenesis (Figure 1). Deacetylation of PGC-1α is only described as stimulating fatty acid oxidation, one could speculate that it may play a role in mitochondrial biogenesis It seems that deacetylation of PGC-1α leads to an increase in mitochondrial content, in a mechanism dependent on Ca2+ , AMPK and Sirt1 [48].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
