Metabolic Regulation of Mitochondrial Protein Biogenesis from a Neuronal Perspective

Abstract

Neurons critically depend on mitochondria for ATP production and Ca2+ buffering. They are highly compartmentalized cells and therefore a finely tuned mitochondrial network constantly adapting to the local requirements is necessary. For neuronal maintenance, old or damaged mitochondria need to be degraded, while the functional mitochondrial pool needs to be replenished with freshly synthesized components. Mitochondrial biogenesis is known to be primarily regulated via the PGC-1α-NRF1/2-TFAM pathway at the transcriptional level. However, while transcriptional regulation of mitochondrial genes can change the global mitochondrial content in neurons, it does not explain how a morphologically complex cell such as a neuron adapts to local differences in mitochondrial demand. In this review, we discuss regulatory mechanisms controlling mitochondrial biogenesis thereby making a case for differential regulation at the transcriptional and translational level. In neurons, additional regulation can occur due to the axonal localization of mRNAs encoding mitochondrial proteins. Hitchhiking of mRNAs on organelles including mitochondria as well as contact site formation between mitochondria and endolysosomes are required for local mitochondrial biogenesis in axons linking defects in any of these organelles to the mitochondrial dysfunction seen in various neurological disorders.

Comprehensive promotion of iPSC-CM maturation by integrating metabolic medium, nanopatterning, and electrostimulation

“…Thus, MAPK/PI3K-AKT inhibition promotes iPSC-CM maturation, partially mediated by the upregulation of PGC-1α 38 . Further research is needed to determine whether the downregulation of MAPK/PI3K signalling pathways in the MM + NP + ES group is involved in PGC-1α and TFAM activation through the control of AMPK 39,36 , AKT 40 and/or mTORC1 41 pathways, and is therefore essential for the metabolic maturation of iPSC-CMs.…”

Mitochondria in the Central Nervous System in Health and Disease: The Puzzle of the Therapeutic Potential of Mitochondrial Transplantation

“…Although highly important for neuronal homeostasis, development, and survival there is limited knowledge on the mechanism evoking mitochondrial biogenesis in neuron endings away from the cell body. One suggestion is that additional regulatory mechanisms have to be involved for axon-localized mitochondrial biogenesis to occur, such as mechanisms that utilize axonal-localized mRNAs translated into mitochondrial proteins and form contacts between mitochondria and endosome/lysosome platforms [ 28 , 29 ]. Although unlikely, there is evidence that mitochondrial biogenesis can occur in the cell body with the new mitochondria transported by an anterograde mechanism while the damaged mitochondria are moved by retrograde transport and then subjected to mitophagy.…”

CLUH maintains functional mitochondria and translation in motoneuronal axons and prevents peripheral neuropathy

“…The long journey of mitochondria to reach peripheral positions makes them susceptible to depletion of short-lived proteins, less flexible to meet metabolic demands via proteome adaptation, and at risk of unbalanced stoichiometry of nuclear-and mitochondrially encoded subunits of the respiratory chain (1). Local translation of mitochondrial proteins in axons is a safeguard mechanism to counteract mitochondrial ageing and preserve their function (2)(3)(4). mRNAs for mitochondrial proteins can be detected in axons, where they are associated with organelles, such as mitochondria and endosomes (5)(6)(7)(8), or in RNA granules in complex with RNA binding proteins (RBPs) (9).…”