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PubMed2025

Mitochondrial dysfunction fuels drug resistance in adult T-cell acute lymphoblastic leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is a relatively rare hematological malignancy, characterized by the uncontrolled proliferation of immature T lymphoblasts and associated with a generally unfavorable prognosis. Our previous research has demonstrated that decreased mitochondrial activity is associated with the aggressiveness of T-ALL tumors. However, the mechanisms underlying this phenomenon and its contribution to treatment resistance remain largely elusive. METHODS: We have built up the largest known T-ALL tumor bank, with a median follow-up of 32 months, including our transcriptomic data from 79 newly sequenced tumors that adds to the 54 publicly accessible samples. Computational analyses and a series of functional assays were performed to investigate the molecular links between altered mitochondrial activity and drug resistance. RESULTS: The transcriptomic analysis revealed that down-regulation of mitochondrial activity is a potent driver of ABCB1 activation, a gene strongly associated with multidrug resistance. In tumors with low mitochondrial activity, the impaired fatty acids β-oxidation leads to intracellular lipid accumulation, which is directly involved in ABCB1 activation. Indeed, our data show that lipid neo-synthesis and accumulation promotes the activation of lipogenic transcription factors, liver X receptors (LXRs), which act as drivers of ABCB1 expression. Tumor data analyses confirmed that high ABCB1 expression in tumour samples is indeed associated with reduced mitochondrial gene expression, lipid droplet enrichment, increased tumour aggressiveness, and significantly shorter patient survival. CONCLUSIONS: Our study demonstrates that reduced mitochondrial activity drives multidrug resistance in adult T-ALL via lipid-mediated activation of ABCB1. These findings enhance our understanding of the biology of aggressive T-ALL and provide insight into mechanisms of resistance to conventional chemotherapy. Consequently, we propose that targeting de novo lipogenesis and restricting dietary fats, such as caprylic acid, may help overcome treatment resistance in patients with T-ALL exhibiting low mitochondrial activity. TRIAL REGISTRATION: The clinical trial was registered under the identifiers ChiCTR-ONRC-14004968 and ChiCTR2000031553 at ClinicalTrials.gov.

Adult↗
PubMed1995

Relationship between free iron level and rat liver mitochondrial dysfunction in experimental dietary iron overload.

The concentration of total iron in the hepatic tissue and mitochondria from rats fed a 2.5% carbonyl iron supplemented diet progressively increased up to 40 days, then reached nearly a steady-state. By contrast the level of free iron (desferrioxamine-chelatable) exhibited a transient but significant increase at 40 days of treatment, only in this period of treatment the induction of lipid peroxidation and the resulting mitochondrial abnormalities in calcium transport was observed too. The enhancement of the energy dissipating mitochondrial calcium cycling was found to be associated with a significant decrease of endogenous mitochondrial ATP content. As to the pathophysiological mechanism for hepatocellular injury in iron overload, these results indicated that the transit pool of free iron may play a critical role in initiating organelle dysfunctions, at least in this experimental model of iron overload.

Animals↗
PubMed2026

Maternal age as a driver of genome instability: mechanisms linking aneuploidy, mutagenesis and mitochondrial dysfunction.

Advanced maternal age is a well-established risk factor for adverse reproductive outcomes due to increased rates of aneuploidy. However, emerging evidence indicates that the genetic consequences of maternal aging extend well beyond chromosome mis-segregation. Aging oocytes acquire a broad spectrum of genetic abnormalities, including maternally derived nuclear de novo mutations (DNMs) and mitochondrial DNA mutations, together with epigenetic dysregulation of DNA methylation and post-translational modification levels. These changes reflect the unique biology of the female germline in which oocytes remain arrested in meiotic prophase I for decades. Age-related deterioration of key processes, such as erosion of cohesion complexes, altered meiotic recombination, and weakened spindle assembly checkpoint surveillance collectively destabilize meiotic chromosome architecture, directly driving chromosome mis-segregation. At the same time, accumulation of endogenous DNA damage and declining DNA damage and repair processes increase the chances of transmitting lesions that can be converted into sequence-level mutations during the earliest embryonic divisions, when genome maintenance relies exclusively on maternal factors. High-resolution sequencing studies further demonstrate that maternal aging is associated with increased DNMs burden in both nuclear and mitochondrial DNA. Together, these findings support a model in which maternal aging is a driver of genome-wide instability that links aneuploidy and mutagenesis through shared defects in meiotic surveillance, declining DNA repair efficiency, and mitochondrial function. This framework positions delayed childbearing as a multifaceted genetic risk factor that extend beyond aneuploidy to include mutations and other genomic alterations that can impact intergenerational genetic risk.

Aneuploidy↗
PubMed1986

Mitochondrial dysfunction and spinocerebellar degenerations.

A simplified classification of the spinocerebellar degenerations is proposed. Axonal ataxias include Friedreich's ataxia and other conditions involving, primarily, neurons with very long axons. Multiple system degenerations include the various olivopontocerebellar atrophies and related disorders. Ataxic encephalopathies are diffuse diseases of the nervous system in which ataxia is a prominent clinical feature. Several lines of data suggest that mitochondrial damage is a common mechanism in the spinocerebellar degenerations. Reasonable pathophysiological mechanisms can be invoked, linking mitochondrial damage to the observed pathologies (including the many cases of intermediate on variant forms).

Ataxia↗
PubMed1986

Consequences of cadmium toxicity in rat hepatocytes: mitochondrial dysfunction and lipid peroxidation.

Cadmium (Cd) (10-100 microM) decreased the ATP/ADP ratio and enhanced lipid peroxidation (LPO) (measured as thiobarbituric acid reactants) in incubated rat hepatocytes. Analysis of the subcellular distribution of Cd indicated its preferential attachment to the inner membranes of mitochondria. Incubation of isolated mitochondria with 0.005-0.05 microM Cd resulted in increased formation of formazans from nitroblue tetrazolium salts, indicating enhanced membrane permeability to succinate. These Cd-concentrations also diminished mitochondrial ATP. LPO in mitochondria strongly increased only after Cd-exposures above 1 microM Cd. Similarly, in Cd-treated hepatocytes decreases in ATP/ADP ratios corresponded to increases in LPO stimulation only at 30 and 60 min but not at 15 min of incubation when ATP/ADP ratios were already affected. Moreover, neither hepatocellular ATP/ADP decrease nor mitochondrial formazan formation due to Cd were prevented by (+)-cyanidanol-3, an effective inhibitor of Cd-induced LPO. These data suggest that even low Cd-concentrations in the hepatocyte disturb the integrity of its mitochondrial membranes concomitantly impairing the hepatocellular energy supply. LPO, only observed at higher Cd-concentrations, is not responsible for these adverse Cd-effects.

Adenosine Diphosphate↗
PubMed1989

Mitochondrial dysfunction in myasthenia gravis. Report of a case.

The case of an 11-year-old boy with external ophthalmoparesia, tetraparesia and bilateral eyelid ptosis is reported. He was 7-years-old when first symptoms appeared. Anticholinesterasic drugs were used. He was submitted to muscle biopsy. The results of histochemistry analysis showed storage of granulous material at the subsarcolemmal region of muscle fibers by SDH. Increase in the number of mitochondria with electron dense bodies was found at electron microscopy. Anticholinesterasic drugs administration was interrupted and consequently he got worse, and bouts of dyspnea occurred. Due to this worsening anticholinesterasic agents were reintroduced together with prednisone, and he improved. Due to clinical and histological expressions we think it is possible that morphological mitochondrial alterations may occur also in myasthenia gravis.

Child↗
PubMed1987

The effect of dilazep on puromycin-induced rat renal mitochondrial dysfunction.

The effect of tetrahydro-1 H-1,4 (5H)-dipropanol bis(3,4,5-trimethoxybenzoate)hydrochloride monohydrate (dilazep, Comelian) on puromycin-induced rat renal damage was investigated. In vivo study: Rats were divided into 3 groups, the control group; untreated, the puromycin group; puromycin (150 mg/kg) was injected intraperitoneally once, the dilazep + puromycin group; puromycin (150 mg/kg) was injected 1 h after intraperitoneal dilazep injection (2 mg/kg), and dilazep (2 mg/kg) was injected every 12 h until the end of the experiment. In each group, 84 h after puromycin injection, kidneys were isolated and renal mitochondria were prepared. The endogenous phospholipase activity in kidney homogenate was determined by high performance liquid chromatography. The activities of three segments (NADH-cytochrome c reductase, succinate-cytochrome c reductase and cytochrome c oxidase) of the electron-transport chain in mitochondria were measured enzymatically. In the puromycin group, phospholipase activity was increased and activities of all of three segments of the electron-transport chain were decreased. In the dilazep + puromycin group, premedication with dilazep prevented activation of phospholipase and maintained mitochondrial electron-transport activity. In vitro study: Mitochondria prepared from intact rat kidney were incubated with phospholipase C. Activities of the mitochondrial electron-transport chain were deteriorated by phospholipase C. These results indicated that activation of endogenous phospholipase, which digests membrane phospholipids, essential components in maintaining mitochondrial electron-transport activity, is responsible for the puromycin-induced renal damage. Premedication with dilazep prevented the damage by inhibition of the activation of phospholipase.

Animals↗
PubMed1988

Prostaglandin I2 analogue and propranolol prevent ischaemia induced mitochondrial dysfunction through the stabilisation of lysosomal membranes.

Leakage of lysosomal enzymes is associated with irreversible cellular damage. To determine the effect of prostaglandin I2 analogue and propranolol on the ischaemic myocardium in relation to changes in lysosomal integrity 26 anaesthetised mongrel dogs were divided into three treatment groups and subjected to 2 h coronary occlusion. In the control group (n = 12) physiological saline was infused throughout the experiment. In the prostaglandin I2 analogue group (n = 7) the prostaglandin I2 analogue, OP-41483-alpha-CD;5(E)-6-Deoxa-6,9 alpha-methylene-15-cyclopentyl-16,17,18,19,20-pentanor-PGI2. alpha-cyclodextrin clathrate (5 ng.kg-1.min-1) was infused from 25 min before occlusion until the end of the experiment. In the propranolol group (n = 7) propranolol (0.3 mg.kg-1) was injected for 10 min 25 min before occlusion. Two hours after occlusion mitochondria were prepared from both ischaemic and non-ischaemic areas in each group and their function measured polarographically with succinate as substrate. Fractionation of myocardial tissue from both non-ischaemic and ischaemic areas was performed and the activities of lysosomal enzymes (N-acetyl-beta-glucosaminidase; beta-glucuronidase) were measured. In the control group, mitochondrial function in the ischaemic area was reduced compared with that from the non-ischaemic area. The activities of both lysosomal enzymes were increased significantly in the supernatant fraction obtained from the ischaemic area compared with those for the supernatant from the non-ischaemic area. The administration of prostaglandin I2 analogue or propranolol not only prevented the leakage of lysosomal enzymes but also maintained mitochondrial function.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Characterization of benzo[a]pyrene quinone-induced toxicity to primary cultured bone marrow stromal cells from DBA/2 mice: potential role of mitochondrial dysfunction.

Oral exposure of DBA/2 mice to benzo[a]pyrene (BP) has been shown to result in hematotoxicity which is manifested as aplastic anemia and leukemia. Since normal hematopoiesis is regulated by bone marrow stromal cells, in this study we have characterized the bone marrow stromal toxicity induced by BP and BP-derived metabolites, particularly quinones. Incubation of stromal cells with various concentrations of BP-1,6-, 3,6-, 6,12-, or 7,8-quinone for 24 hr resulted in a significant decrease of cell survival in a concentration-dependent manner, while cells treated with BP or BP-7,8-dihydrodiol did not exhibit any significant loss of cell survival. Among the BP quinones examined, BP-1,6-quinone was the most cytotoxic to stromal cells. The cytotoxicity induced by BP-1,6-quinone also exhibited a time-dependent relationship. Pretreatment of stromal cells with 1,2-dithiole-3-thione (D3T) resulted in a significant induction of both cellular reduced glutathione (GSH) content and quinone reductase (QR) activity in a concentration-dependent manner. However, D3T pretreatment did not offer any protection against BP-1,6-quinone-induced toxicity. Furthermore, dicumarol, a potent inhibitor of QR, or buthionine sulfoximine, a specific inhibitor of GSH biosynthesis, did not potentiate BP-1,6-quinone-induced cytotoxicity was not altered. However, incubation of stromal cells with BP-1,6-quinone resulted in a significant depletion of cellular ATP content and mitochondrial morphological changes, which preceded the loss of cell survival. In addition to BP-1,6-quinone, other cytotoxic BP quinones also exhibited a capacity to deplete cellular ATP level in stromal cells, while BP, which was not cytotoxic to stromal cells, did not elicit any significant decrease in cellular ATP level. These observations suggest that mitochondria may be a potential target of BP quinones. Overall, the above results indicate that neither cellular GSH and QR nor reactive oxygen species appear to be involved in BP quinone-induced stromal cell injury and that BP quinones may elicit cytotoxicity to stromal cells through directly disrupting mitochondrial energy metabolism.

Adenosine Triphosphate↗
PubMed1992

The binding of bridged bis-pyridinium oximes to DNA and its relevance to the induction of mitochondrial dysfunction in yeast.

Bis-pyridium oximes and methoximes from a newly synthesized series are weak DNA binders (K = 3.10(4) M-1 under physiological conditions). From the number of binding sites per phosphate, 0.25, the ionic strength dependence of the binding constant and the negative electric dichroism, it is concluded that monointercalation is the mode of association. In contrast to methoxy compounds, the oxime derivatives are able both to induce the mutated "petite" phenotype in yeast S. cerevisiae and to cause "in vitro" extensive condensation of single stranded DNA. This reaction is postulated to be relevant to the mutational process that leads to "peptide" cells. The absence of nuclear mutation is interpreted in terms of sequestration of the drug in mitochondria under the effect of the organelle inner membrane electrochemical potential.

Animals↗