Mitochondria are the powerhouse of the cell and the primary source of cellular energy production under aerobic conditions. The process involves reducing equivalents from intermediary metabolism, which donate electrons to the respiratory chain’s complex I, III, and IV, pumping protons from the matrix to the intermembrane space.
The resulting electrochemical force is utilized by complex V to regenerate ATP through oxidative phosphorylation (OXPHOS), which is required for all active cellular processes. While most of the mitochondrial proteome is encoded by the nuclear genome, thirteen essential respiratory chain proteins are encoded by the mitochondrial genome, which is inherited independently down the maternal line.
A new study published in the Cell sheds light on how different tissues and organs have varying capacities for oxidative ATP production, reflecting their energy dependence. The study shows cell lineage-specific transcriptional profiles emerge as early as embryonic day 8.5 in mice, including organ-specific mitochondrial protein isoforms before organogenesis is complete.
The coordinated and close cooperation between the nuclear and mitochondrial genomes is essential for aerobic ATP production, and disruption in intra-mitochondrial protein synthesis down-regulated nuclear genes known to buffer the effects of mitochondrial toxins when knocked out in vitro, thus maintaining cell lineage viability during in vivo development.
Researchers revealed that one method that compensates for mitochondrial failure during key early embryonic developmental phases involves transcription factors known to influence gene networks using single-cell transcriptome analysis. These findings show that nuclear-mitochondrial crosstalk is established in early mammalian development, long before organ maturation, providing resistance to mitochondrial insults and likely contributing to the organ-specific vulnerability that characterizes rare genetic mitochondrial diseases and common human disorders that involve mitochondrial mechanisms.
This discovery, which emphasizes the necessity of knowing the relationship between nuclear and mitochondrial genomes for cellular survival, may inspire new approaches to treating human disorders associated with mitochondrial malfunction.
Defects in the intra-mitochondrial translation are a common cause of rare inherited mitochondrial disorders, affecting approximately 1 in 8,000 humans. Despite a shared biochemical defect of oxidative phosphorylation (OXPHOS), there is considerable clinical heterogeneity among these diseases, with strikingly different phenotypes observed in patients with closely related mutations affecting the mtDNA-encoded tRNA genes.
The reasons for this heterogeneity are not well understood, but the different properties of mitochondria found in different cell types have been proposed as an explanation for patterns of organ involvement. By E8.5, five base pair variations in pathogenic mt-Ta mutations in mice resulted in distinct nuclear transcriptional responses in different cell lineages. This implies that similar mechanisms are at work during fetal development in a number of human mitochondrial disorders defined by tissue selectivity.
Signals from the mitochondrion to the cell nucleus are poorly understood. Still, they are likely to occur at multiple levels, including ATP, the cellular redox state, organellar calcium release, tricarboxylic acid intermediates, amino acid, and one-carbon metabolism, and the mitochondrial unfolded protein response (UPRmt,) and ISRmt. It needs to be clear how different mtDNA mutations could induce different nuclear transcriptional responses.
Several genes whose expression was lowered owing to mt-Ta mutations were discovered to be shut down in vitro, shielding cell lines against mitochondrial toxins. This has the potential to explain the age-old puzzle of why certain severe OXPHOS illnesses do not manifest until later in lif when therapy is no longer available. The study also discovered novel transcriptional elements that govern a variety of buffering functions, paving the way for systemic therapies against known druggable targets that have a strong effect on one tissue while having little effect on others.
Despite the fact that the UPRmt and its associated ISRmt have been connected to the pathogenesis of mitochondrial diseases, our study found no increase in ISR transcripts in any of the cell lineages present in E8.5 mt-Ta animals. Yet, new datahaves elucidated the ISRmt’s temporal dynamics, showing three different stages defined by local and systemic effects that arise gradually and are partially reliant on FGF21.
These stages are broken down as follows: These findings imply that the postulated mechanisms in the study may constitute appealing treatment and prevention methods for mitochondrial diseases. One example of these pathways is transcription factors linked with stress responses that are not part of the classical innate stress response.
