Edited by Yau-Huei Wei and Wan-Wan Lin
A thematic series in Journal of Biomedical Science.
In this thematic issue, we have included review articles and research papers that addressed important questions in mitochondrial biology and human diseases caused by mitochondrial dysfunction. The advances in mitochondrial biology over the past two decades have greatly expanded our understanding of the roles that mitochondria play in health and disease of the humans. Mitochondria have their own DNA (mtDNA), which is transmitted through the maternal lineage. Mitochondrial diseases can be caused by gene mutations in nuclear DNA or mtDNA or both. LHON, MERRF, and MELAS syndromes are caused by point mutations in structural genes or tRNA genes in mtDNA, and large-scale deletions of mtDNA lead to Kearns-Sayre syndrome and Pearson syndrome. The mutated and wild-type mtDNA often coexist in the affected tissues, a condition termed heteroplasmy. In a research paper, Dr. Min-Xin Guan’s group showed that the deleterious effects of m.14484T>C mutation in the ND6 gene of mtDNA causing LHON could be remedied by allotopic expression of ND6 transgene in a cybrid model. The ND6 transgene was generated by changing codons and added to a mitochondria-targeting sequence of COX8. Stable transfectants were generated by transferring the ND6 cDNA expressed in a pCDH-puro vector into the cybrids with and without the m.14484T>C mutation, respectively. The overexpression of ND6 led to increases in Complex I activity, ATP level and ΔΨm as well as reduction of the reactive oxygen species (ROS) and apoptosis in the transfected cybrids harboring m.14484T>C mutation. The study demonstrated that allotopic expression of ND6 gene can restore mitochondrial function and suppress the m.14484T>C mutation-induced oxidative stress and apoptosis. This gene editing approach may help develop novel therapy for mitochondrial diseases. In another research paper, Dr. Yu-Ting Wu and coworkers established a protocol to enable the induced pluripotent stem cells (iPSCs) from several patients with MERRF syndrome to differentiate into neural progenitor cells and cortical neurons. They demonstrated that the neurons harboring medium to high levels of m.8344A>G mutation exhibited mitochondrial dysfunction, ROS overproduction, imbalanced expression of antioxidant enzymes, decreased synaptic plasticity and neuro-transmission defects. The iPSCs platform could recapitulate genetic, biochemical and electrophysiological defects underlying neurological disorders frequently observed in patients with MERRF syndrome. This study also demonstrated that new variants of mtDNA can be generated and the pathogenic mtDNA mutation load is drifted in the subculture and differentiation of iPSCs, and recommended that whole mitochondrial genome sequencing be included in the quality control of iPSCs and iPSCs-derived cell lineages before using them as the disease model. In consideration of the successful applications of iPSCs in modeling human diseases, Dr. Chao Chen and Dr. Min-Xin Guan reviewed the recent advances in patients-derived iPSCs as ex vivo models for elucidation of pathogenic mechanism and gene editing for correction of mtDNA mutation causing mitochondrial diseases. The iPSCs have been differentiated into various specific lineages of cells such as cardiomyocytes, neurons, retinal ganglion cells, and inner ear hair cells, respectively, to model the pathologies and clinical phenotypes manifested in the patients. The iPSCs from patients with a large-scale deletion of mtDNA causing Pearson syndrome or Kearns Sayre syndrome and point mutations of mtDNA causing MELAS, MERRF, LHON, Leigh syndrome, and maternally inherited deafness, respectively, have provided new opportunities for us to study the pathophysiology and multisystem disorders of these mitochondrial diseases and to facilitate the development of novel therapeutic approaches for better treatment.
In a review article, Dr. Hsin-Chen Lee and associates provided an updated review on the roles of mitochondrial dysfunction and mutations of mtDNA and metabolic switch in the progression of human cancers. Mitochondrial alterations might activate mitochondrial retrograde signaling and stress response pathways through ROS, Ca2+, or oncometabolites in cancer progression. They also reviewed the roles of mitochondria in the immune regulatory function of immune cells, the cancer immunity in tumor microenvironment, and cancer immunotherapy. These advances suggest that targeting the mitochondrial retrograde signaling and metabolism might lead to novel strategies for cancer treatment. Metabolic reprogramming often occurs during the progression or metastasis of cancer cells, and abundant evidence has substantiated the notion that metabolic plasticity and adaptability of cancer cells play an important role in cancer progression and resistance to chemotherapy. Mitophagy is a conserved biological function in the mammalian cells that plays a key role in the quality control of mitochondria. A defect in mitochondrial turnover may result in human disease. The review contributed by Dr. Quan Chen and colleagues focused on the coordination between mitophagy and mitochondrial biogenesis and the signaling pathways involved in these two opposing processes in the response of tissue or cultured cells to energy needs, stress or pathophysiological conditions. Notably, defects in the Parkin-PINK 1 axis affected transcription and replication of mtDNA, and in turn biogenesis and homeostasis of mitochondria. They highlighted the crosstalk between them in the maintenance of optimal cellular fitness and function under altered environmental or physiological conditions, which may help us fight aging and neurodegenerative diseases. Another review article contributed by Dr. Wei-yuan Yang and coworkers focused on the release of intracellular materials and even dysfunctional mitochondria into the extracellular space for degradation. Recent studies revealed an interplay between intracellular mitochondrial degradation pathways and extracellular mitochondrial release in the quality control of mitochondria. Neuronal cells and mesenchymal stem cells can release mitochondria-containing extracellular vesicles (EVs) to enhance bioenergetic function of recipient cells, such as in the activation of immune cells. Interestingly, neurons can release and transfer aberrant mitochondria in the EVs called migrasomes to adjacent astrocytes for degradation. Selective release of dysfunctional mitochondria mediated by migrasomes plays a role in quality control of mitochondria. This line of research has provided new insights for us to better understand the extracellular release and transfer of mitochondria in the quality control of these organelles in human health and disease.
With the research papers and review articles included in this issue, we want to emphasize the potential use of new approaches to treat mitochondrial diseases caused by mtDNA mutations and study the molecular basis of their pathophysiology by using iPSCs-derived cell lineages such as neurons and cardiomyocytes that are not accessible from patients. The two review articles on mitophagy and release of EVs and mitochondria mediated by migrasomes have provided integrated view on the mechanistic details of mitochondrial quality control and its importance in the homeostasis of mitochondria and fitness of the cells. We hope that this thematic issue will draw more attention of biomedical researchers and clinicians to the increasing importance and multifaceted roles of mitochondria in biology and clinical medicine.