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.

Keywords: AMPK; PGC-1α; insulin; mTORC1; mitochondrial biogenesis; neurons; transcription; translation.

Figure 1

Regulation of mitochondrial biogenesis at the transcriptional and translational level. At the transcriptional level, the PGC-1α-NRF-1/2-TFAM pathway is the master regulator of mitochondrial biogenesis. Increased AMP/ATP ratio, NAD⁺/NADH ratio and Ca²⁺ levels, which are part of mitochondrial feedback mechanisms within the cell, result in activation of AMPK, PKA, SIRT1 and CaMK that in turn lead to PGC-1α stimulation. Once activated, PGC-1α promotes transcription of nuclear-encoded mitochondrial genes via NRF-1/2 and transcription of mitochondrial-encoded genes via expression of TFAM. At the translational level, the insulin-induced PI3K/AKT/mTORC1 pathway plays a major role in mitochondrial biogenesis. Via activation of eIF4E, mTORC1 increases the translation of nuclear-encoded mitochondrial proteins, which are imported into mitochondria. AKT, however, also has an effect on transcription via inhibition of FOXO1 and consequent activation of PGC-1α. Furthermore, AMPK is also a substrate of AKT, which is inhibited by AKT-induced phosphorylation. Finally, AMPK and mTORC1 can inhibit each other by direct phosphorylation.

Figure 2

Transport of nuclear-encoded mitochondrial transcripts in neurons. Motor proteins actively transport RNA granules, mitochondria and Rab5-positive early endosomes as well as Rab7- and LAMP1-positive endolysosomes along axons. In this way, nuclear-encoded mitochondrial transcripts that are either part of RNA granules or tethered to the organelles reach distal parts of the neurons allowing for local translation. (A) The mitochondrial laminb2 and bclw transcripts are transported in RNA granules via binding to their RBP SFPQ. Cox7c and Pink1 mRNA are tethered to mitochondria. The tethering complex for Pink1 mRNA is composed of SYNJ2BP and SYNJ2. (B) Several mRNAs are transported with early endosomes. The FERRY complex localizes to early endosomes and interacts both with the translation machinery and mRNAs that are enriched for nuclear-encoded mitochondrial genes. (C) Endolysosomes transport G3BP1-containing RNA granules using ANXA11 as a tether.