bims-mitmed 2024-11-10 papers

Issue of 2024‒11‒10
nine papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Nat Commun. 2024 Nov 01. 15(1): 9438

Transfer of mitochondrial DNA into the nuclear genome during induced DNA breaks.

Jinchun Wu, Yang Liu, Liqiong Ou, Tingting Gan, Zhengrong Zhangding, Shaopeng Yuan, Xinyi Liu, Mengzhu Liu, Jiasheng Li, Jianhang Yin, Changchang Xin, Ye Tian, Jiazhi Hu.

Mitochondria serve as the cellular powerhouse, and their distinct DNA makes them a prospective target for gene editing to treat genetic disorders. However, the impact of genome editing on mitochondrial DNA (mtDNA) stability remains a mystery. Our study reveals previously unknown risks of genome editing that both nuclear and mitochondrial editing cause discernible transfer of mitochondrial DNA segments into the nuclear genome in various cell types including human cell lines, primary T cells, and mouse embryos. Furthermore, drug-induced mitochondrial stresses and mtDNA breaks exacerbate this transfer of mtDNA into the nuclear genome. Notably, we observe that mitochondrial editors, including mitoTALEN and recently developed base editor DdCBE, can also enhance crosstalk between mtDNA and the nuclear genome. Moreover, we provide a practical solution by co-expressing TREX1 or TREX2 exonucleases during DdCBE editing. These findings imply genome instability of mitochondria during induced DNA breaks and explain the origins of mitochondrial-nuclear DNA segments.

DOI: https://doi.org/10.1038/s41467-024-53806-0

Proc Natl Acad Sci U S A. 2024 Nov 19. 121(47): e2414187121

Cytosolic N6AMT1-dependent translation supports mitochondrial RNA processing.

Mads M Foged, Emeline Recazens, Sylvain Chollet, Miriam Lisci, George E Allen, Boris Zinshteyn, Doha Boutguetait, Christian Münch, Vamsi K Mootha, Alexis A Jourdain.

Mitochondrial biogenesis relies on both the nuclear and mitochondrial genomes, and imbalance in their expression can lead to inborn errors of metabolism, inflammation, and aging. Here, we investigate N6AMT1, a nucleo-cytosolic methyltransferase that exhibits genetic codependency with mitochondria. We determine transcriptional and translational profiles of N6AMT1 and report that it is required for the cytosolic translation of TRMT10C (MRPP1) and PRORP (MRPP3), two subunits of the mitochondrial RNAse P enzyme. In the absence of N6AMT1, or when its catalytic activity is abolished, RNA processing within mitochondria is impaired, leading to the accumulation of unprocessed and double-stranded RNA, thus preventing mitochondrial protein synthesis and oxidative phosphorylation, and leading to an immune response. Our work sheds light on the function of N6AMT1 in protein synthesis and highlights a cytosolic program required for proper mitochondrial biogenesis.

Keywords: OXPHOS; RNA processing; mitochondria; mitochondrial RNA granules; translation

DOI: https://doi.org/10.1073/pnas.2414187121

Pharmacol Res. 2024 Oct 30. pii: S1043-6618(24)00429-8. [Epub ahead of print] 107484

USP14 inhibition enhances Parkin-independent mitophagy in iNeurons.

Bernardo Greta, A Prado Miguel, Dashtmian Anna Roshani, Mariavittoria Favaro, Sofia Mauri, Alice Borsetto, Elena Marchesan, Joao A Paulo, Steve P Gygi, Daniel J Finley, Elena Ziviani.

Loss of proteostasis is well documented during physiological aging and depends on the progressive decline in the activity of two major degradative mechanisms: the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway. This decline in proteostasis is exacerbated in age-associated neurodegenerative diseases, such as Parkinson's Disease (PD). In PD, patients develop an accumulation of aggregated proteins and dysfunctional mitochondria, which leads to ROS production, neuroinflammation and neurodegeneration. We recently reported that inhibition of the deubiquitinating enzyme USP14, which is known to enhance both the UPS and autophagy, increases lifespan and rescues the pathological phenotype of two Drosophila models of PD. Studies on the effects of USP14 inhibition in mammalian neurons have not yet been conducted. To close this gap, we exploited iNeurons differentiated from human embryonic stem cells (hESCs), and investigated the effect of inhibiting USP14 in these cultured neurons. Quantitative global proteomics analysis performed following genetic ablation or pharmacological inhibition of USP14 demonstrated that USP14 loss of function specifically promotes mitochondrial autophagy in iNeurons. Biochemical and imaging data also showed that USP14 inhibition enhances mitophagy. The mitophagic effect of USP14 inhibition proved to be PINK1/Parkin- independent, instead relying on expression of the mitochondrial E3 Ubiquitin Ligase MITOL/MARCH5. Notably, USP14 inhibition normalized the mitochondrial defects of Parkin KO human neurons.

Keywords: Autophagy; MARCH5/MITOL; Mitophagy; PINK1; Parkin; UPS; USP14

DOI: https://doi.org/10.1016/j.phrs.2024.107484

Nature. 2024 Nov 06.

Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.

Keun Woo Ryu, Tak Shun Fung, Daphne C Baker, Michelle Saoi, Jinsung Park, Christopher A Febres-Aldana, Rania G Aly, Ruobing Cui, Anurag Sharma, Yi Fu, Olivia L Jones, Xin Cai, H Amalia Pasolli, Justin R Cross, Charles M Rudin, Craig B Thompson.

Mitochondria serve a crucial role in cell growth and proliferation by supporting both ATP synthesis and the production of macromolecular precursors. Whereas oxidative phosphorylation (OXPHOS) depends mainly on the oxidation of intermediates from the tricarboxylic acid cycle, the mitochondrial production of proline and ornithine relies on reductive synthesis1. How these competing metabolic pathways take place in the same organelle is not clear. Here we show that when cellular dependence on OXPHOS increases, pyrroline-5-carboxylate synthase (P5CS)-the rate-limiting enzyme in the reductive synthesis of proline and ornithine-becomes sequestered in a subset of mitochondria that lack cristae and ATP synthase. This sequestration is driven by both the intrinsic ability of P5CS to form filaments and the mitochondrial fusion and fission cycle. Disruption of mitochondrial dynamics, by impeding mitofusin-mediated fusion or dynamin-like-protein-1-mediated fission, impairs the separation of P5CS-containing mitochondria from mitochondria that are enriched in cristae and ATP synthase. Failure to segregate these metabolic pathways through mitochondrial fusion and fission results in cells either sacrificing the capacity for OXPHOS while sustaining the reductive synthesis of proline, or foregoing proline synthesis while preserving adaptive OXPHOS. These findings provide evidence of the key role of mitochondrial fission and fusion in maintaining both oxidative and reductive biosyntheses in response to changing nutrient availability and bioenergetic demand.

DOI: https://doi.org/10.1038/s41586-024-08146-w

Brain. 2024 Nov 06. pii: awae277. [Epub ahead of print]

Phase 2b program with sonlicromanol in patients with mitochondrial disease due to m.3243A>G mutation.

Mitochondrial disease is a group of rare conditions, with no approved treatment to date, except for Leber hereditary optic neuropathy. Therapeutic options to alleviate the symptoms of mitochondrial disease are urgently needed. Sonlicromanol is a promising candidate, as it positively alters the key metabolic and inflammatory pathways associated with mitochondrial disease. Sonlicromanol is a reductive and oxidative distress modulator, selectively inhibiting microsomal prostaglandin E1 synthase activity. This Phase 2b program, aiming at evaluating sonlicromanol in adults with m.3243A>G mutation and primary mitochondrial disease, consisted of a randomized controlled (RCT) study (dose-selection) followed by a 52-week open-label extension study (EXT, long-term tolerability, safety, and efficacy of sonlicromanol). Patients were randomized (1:1:1) to receive 100- or 50-mg sonlicromanol, or placebo twice daily (bid) for 28 days with ≥2-week wash-out period between treatments. Patients who completed the RCT study entered the EXT study wherein they received 100-mg sonlicromanol bid. Overall, 27 patients were randomized (24 RCT patients completed all periods). 15 patients entered the EXT, and 12 patients were included in the EXT analysis set. All patients reported good tolerability and favourable safety, with pharmacokinetic results comparable to the earlier Phase 2a study. The RCT primary endpoint (change from placebo in the attentional domain of cognition score [IDN: visual identification, Cogstate]) did not reach statistical significance. Using a categorisation of the subject's period baseline a treatment effect over placebo was observed if their baseline was more affected (p=0.0338). Using this approach, there were signals of improvements over placebo in at least one dose in the Beck Depression Inventory (BDI, p=0.0143), Cognitive Failure Questionnaire (CFQ, p=0.0113), and the Depression subscale of the Hospital Anxiety and Depression Scale (p=0.0256). Statistically and/or clinically meaningful improvements were observed in the patient- and clinician-reported outcome measures at the end of the EXT study (Test of attentional performance [TAP] with alarm, p=0.0102; TAP without alarm, p=0.0047; BDI somatic, p=0.0261; BDI Total, p=0.0563; SF12 physical component score, p=0.0008). Seven of nine domains of RAND-Short form-36 like SF-36 pain improved (p=0.0105). Other promising results were observed in Neuro QoL-Fatigue-SF (p=0.0036), MiniBESTest (p=0.0009), McGill Pain Questionnaire (p=0.0105), EQ-5D-5L-VAS (p=0.0213) and EQ-5D-5L-index (p=0.0173). Most patients showed improvement in the 5× sit-to-stand test. Sonlicromanol was well-tolerated and demonstrated a favourable benefit/risk ratio for up to one year. Sonlicromanol was efficacious in patients when affected at baseline, as seen across a variety of clinically relevant domains. Long-term treatment showed more pronounced changes from baseline.

Keywords: MELAS; MIDD; m.3243A>G; primary mitochondrial disease; sonlicromanol

DOI: https://doi.org/10.1093/brain/awae277

Ageing Res Rev. 2023 Oct 28. pii: S1568-1637(23)00265-9. [Epub ahead of print] 102106

NAD+: An Old but Promising Therapeutic Agent for Skeletal Muscle Ageing.

Yingying Xu, Weihua Xiao.

More than a century after the discovery of nicotinamide adenine dinucleotide (NAD+), our understanding of the molecule's role in the biology of ageing continues to evolve. As a coenzyme or substrate for many enzymes, NAD+ governs a wide range of biological processes, including energy metabolism, genomic stability, signal transduction, and cell fate. NAD+ deficiency has been recognised as a bona fide hallmark of tissue degeneration, and restoring NAD+ homeostasis helps to rejuvenate multiple mechanisms associated with tissue ageing. The progressive loss of skeletal muscle homeostasis with age is directly associated with high morbidity, disability and mortality. The aetiology of skeletal muscle ageing is complex, involving mitochondrial dysfunction, senescence and stem cell depletion, autophagy defects, chronic cellular stress, intracellular ion overload, immune cell dysfunction, circadian clock disruption, microcirculation disorders, persistent denervation, and gut microbiota dysbiosis. This review focuses on the therapeutic potential of NAD+ restoration to alleviate the above pathological factors and discusses the effects of in vivo administration of different NAD+ boosting strategies on skeletal muscle homeostasis, aiming to provide a reference for combating skeletal muscle ageing.

Keywords: NAD(+) boosting; NAD(+) metabolism; Skeletal muscle ageing; Therapies

DOI: https://doi.org/10.1016/j.arr.2023.102106

Placenta. 2024 Oct 15. pii: S0143-4004(24)00677-5. [Epub ahead of print]158 217-222

Impact of autologous mitochondrial transfer on obstetric and neonatal health of offspring: A small single-center case series.

Julia Gil, Mar Nohales, David Ortega-Jaen, Angel Martin, M L Pardiñas, Vicente Serra, Elena Labarta, Maria José de Los Santos.

INTRODUCTION: A pilot study was carried out to test the efficacy of the autologous mitochondrial transfer therapy (AUGMENT) technique. No improvements in pregnancy rate, development, or embryo quality were observed in the AUGMENT-treated group versus the Control group in this study. The main objective of this research is to analyze whether AUGMENT technology did have any impact on the obstetric and perinatal outcomes of pregnancies and children resulting from treated oocytes.METHODS: Follow up study of women with a livebirth who participated in a pilot randomized controlled trial in which sibling MII oocytes were randomly allocated to AUGMENT + intracytoplasmic sperm injection (ICSI) (AUGMENT group) or ICSI alone (control group). Preimplantation genetic testing for aneuploidy was performed in both groups. Pregnancy and neonatal outcomes of 14 women (15 pregnancies) and their 18 children were analyzed. The information was retrieved by reviewing the medical records or through questionnaires sent to the patients.
RESULTS: No differences were found in this small case series between the AUGMENT and control groups regarding the rate of gestational complications, birth defects, gestational age at delivery (271.4 ± 12.56 vs 278 ± 10.4 days), birthweight (3.1 ± 0.6 kg vs. 3.1 ± 0.4 kg) and neonatal outcome.
DISCUSSION: The few pregnancies achieved using AUGMENT oocyte therapy had similar outcomes than controls in this very small series. Our very preliminary data need to be confirmed in larger samples. The long term follow up of these children also needs to be analyzed.

Keywords: AUGMENT; Mitochondrial transfer; Pregnancy

DOI: https://doi.org/10.1016/j.placenta.2024.10.007