bims-mikwok 2023-02-26 papers

Issue of 2023‒02‒26
five papers selected by
Avinash N. Mukkala, University of Toronto

J Muscle Res Cell Motil. 2023 Feb 18.

Xenogeneic transplantation of mitochondria induces muscle regeneration in an in vivo rat model of dexamethasone-induced atrophy.

Mi Jin Kim, Ji Min Lee, Kyunghoon Min, Yong-Soo Choi.

Muscle atrophy significantly impairs health and quality of life; however, there is still no cure. Recently, the possibility of regeneration in muscle atrophic cells was suggested through mitochondrial transfer. Therefore, we attempted to prove the efficacy of mitochondrial transplantation in animal models. To this end, we prepared intact mitochondria from umbilical cord-derived mesenchymal stem cells maintaining their membrane potential. To examine the efficacy of mitochondrial transplantation on muscle regeneration, we measured muscle mass, cross-sectional area of muscle fiber, and changes in muscle-specific protein. In addition, changes in the signaling mechanisms related to muscle atrophy were evaluated. As a result, in mitochondrial transplantation, the muscle mass increased by 1.5-fold and the lactate concentration decreased by 2.5-fold at 1 week in dexamethasone-induced atrophic muscles. In addition, a 2.3-fold increase in the expression of desmin protein, a muscle regeneration marker, showed a significant recovery in MT 5 µg group. Importantly, the muscle-specific ubiquitin E3-ligases MAFbx and MuRF-1 were significantly decreased through AMPK-mediated Akt-FoxO signaling pathway by mitochondrial transplantation compared with the saline group, reaching a level similar to that in the control. Based on these results, mitochondrial transplantation may have therapeutic applications in the treatment of atrophic muscle disorders.

Keywords: Dexamethasone; Mitochondria; Mitochondrial dysfunction; Mitochondrial transplantation; Muscle atrophy; Muscle regeneration

DOI: https://doi.org/10.1007/s10974-023-09643-7

Autophagy. 2023 Feb 20.

The role of programmed mitophagy in germline mitochondrial DNA quality control.

Jonathan M Palozzi, Thomas R Hurd.

Mitochondrial DNA (mtDNA) is prone to the accumulation of mutations. To prevent harmful mtDNA mutations from being passed on to the next generation, the female germline, through which mtDNA is exclusively inherited, has evolved extensive mtDNA quality control. To dissect the molecular underpinnings of this process, we recently performed a large RNAi screen in Drosophila and uncovered a programmed germline mitophagy (PGM) that is essential for mtDNA quality control. We found that PGM begins as germ cells enter meiosis, induced, at least in part, by the inhibition of the mTor (mechanistic Target of rapamycin) complex 1 (mTorC1). Interestingly, PGM requires the general macroautophagy/autophagy machinery and the mitophagy adaptor BNIP3, but not the canonical mitophagy genes Pink1 and park (parkin), even though they are critical for germline mtDNA quality control. We also identified the RNA-binding protein Atx2 as a major regulator of PGM. This work is the first to identify and implicate a programmed mitophagy event in germline mtDNA quality control, and it highlights the utility of the Drosophila ovary for studying developmentally regulated mitophagy and autophagy in vivo.

Keywords: Drosophila; autophagy; germline; mitochondria; mitochondrial DNA; mitophagy; mtDNA; purifying selection

DOI: https://doi.org/10.1080/15548627.2023.2182595

Cell. 2023 Feb 17. pii: S0092-8674(23)00093-4. [Epub ahead of print]

Cell lineage-specific mitochondrial resilience during mammalian organogenesis.

Mitochondrial activity differs markedly between organs, but it is not known how and when this arises. Here we show that cell lineage-specific expression profiles involving essential mitochondrial genes emerge at an early stage in mouse development, including tissue-specific isoforms present before organ formation. However, the nuclear transcriptional signatures were not independent of organelle function. Genetically disrupting intra-mitochondrial protein synthesis with two different mtDNA mutations induced cell lineage-specific compensatory responses, including molecular pathways not previously implicated in organellar maintenance. We saw downregulation of genes whose expression is known to exacerbate the effects of exogenous mitochondrial toxins, indicating a transcriptional adaptation to mitochondrial dysfunction during embryonic development. The compensatory pathways were both tissue and mutation specific and under the control of transcription factors which promote organelle resilience. These are likely to contribute to the tissue specificity which characterizes human mitochondrial diseases and are potential targets for organ-directed treatments.

Keywords: OXPHOS; RNA-seq; SCENIC; mitochondria; mt-Ta; mtDNA; organogenesis; single-cell

DOI: https://doi.org/10.1016/j.cell.2023.01.034

bioRxiv. 2023 Feb 13. pii: 2023.02.11.528148. [Epub ahead of print]

The Small GTPase Rab7 Regulates Release of Mitochondria in Extracellular Vesicles in Response to Lysosomal Dysfunction.

Wenjing Liang, Rachel Y Diao, Justin M Quiles, Rita H Najor, Liguo Chi, Benjamin P Woodall, Leonardo J Leon, Jason Duran, David M Cauvi, Antonio De Maio, Eric D Adler, Ã Sa B Gustafsson.

Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.

DOI: https://doi.org/10.1101/2023.02.11.528148

Mol Ther. 2023 Feb 18. pii: S1525-0016(23)00079-5. [Epub ahead of print]

Delivery of mitochondria confers cardioprotection through mitochondria replenishment and metabolic compliance.

Alian Zhang, Yangyang Liu, Jianan Pan, Francesca Pontanari, Andrew Chia-Hao Chang, Honghui Wang, Shuang Gao, Changqian Wang, Alex Cy Chang.

Mitochondrial dysfunction is a hallmark of heart failure. Mitochondrial transplantation has been demonstrated to be able to restore heart function but its mechanism of action remains unresolved. Using an in-house optimized mitochondrial isolation method, we tested efficacy of mitochondria transplantation in two different heart failure models. First using the doxorubicin-induced heart failure model, we demonstrate that mitochondrial transplantation prior to doxorubicin challenge protects cardiac function in vivo, prevents myocardial apoptosis, but contraction improvement relies on the metabolic compatibility between transplanted mitochondria and treated cardiomyocytes. Second, using mutation driven dilated cardiomyopathic human induced pluripotent stem cell-derived cardiomyocyte model, we demonstrate that mitochondrial transplantation preferentially boosts contraction in ventricular myocytes. Last, using single cell RNASeq, we show that mitochondria transplantation boosts contractility in dystrophic cardiomyocytes with little transcriptomic alterations. Together, we provide evidence that mitochondria transplantation confers myocardial protection and may serve as a potential therapeutic option for heart failure.

Keywords: dilated cardiomyopathy; doxorubicin; iPSC; mitochondria delivery

DOI: https://doi.org/10.1016/j.ymthe.2023.02.016