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Mitochondrial diseases comprise a common group of neurometabolic disorders resulting from OXPHOS defects, that may manifest with neurological impairments, for which there are currently no disease-modifying therapies. Previous studies suggest inhibitory interneuron susceptibility to mitochondrial impairment, especially of parvalbumin-expressing interneurons (PV+). We have developed a mouse model of mitochondrial dysfunction specifically in PV+ cells via conditional Tfam knockout, that exhibited a juvenile-onset progressive phenotype characterised by cognitive deficits, anxiety-like behaviour, head-nodding, stargazing, ataxia, and reduced lifespan. A brain region-dependent decrease of OXPHOS complexes I and IV in PV+ neurons was detected, with Purkinje neurons being most affected. We validated these findings in a neuropathological study of patients with pathogenic mtDNA and POLG variants showing PV+ interneuron loss and deficiencies in complexes I and IV. This mouse model offers a drug screening platform to propel the discovery of therapeutics to treat severe neurological impairment due to mitochondrial dysfunction. The establishment of a mouse model of mitochondrial dysfunction in parvalbumin-expressing interneurons, resembling mitochondrial and cognitive defects observed in patients, provides a route for drug screening towards a therapeutic avenue for neurological impairment. [ABSTRACT FROM AUTHOR]

Mitochondrial diseases represent the most common inherited neurometabolic disorders, for which no effective therapy currently exists for most patients. The unmet clinical need requires a more comprehensive understanding of the disease mechanisms and the development of reliable and robust in vivo models that accurately recapitulate human disease. This review aims to summarise and discuss various mouse models harbouring transgenic impairments in genes that regulate mitochondrial function, specifically their neurological phenotype and neuropathological features. Ataxia secondary to cerebellar impairment is one of the most prevalent neurological features of mouse models of mitochondrial dysfunction, consistent with the observation that progressive cerebellar ataxia is a common neurological manifestation in patients with mitochondrial disease. The loss of Purkinje neurons is a shared neuropathological finding in human post-mortem tissues and numerous mouse models. However, none of the existing mouse models recapitulate other devastating neurological phenotypes, such as refractory focal seizures and stroke-like episodes seen in patients. Additionally, we discuss the roles of reactive astrogliosis and microglial reactivity, which may be driving the neuropathology in some of the mouse models of mitochondrial dysfunction, as well as mechanisms through which cellular death may occur, beyond apoptosis, in neurons undergoing mitochondrial bioenergy crisis. [ABSTRACT FROM AUTHOR]

One of the hallmarks of aging is an accumulation of cells with defects in oxidative phosphorylation (OXPHOS) due to mutations of mitochondrial DNA (mtDNA). Rapidly dividing tissues maintained by stem cells, such as the colonic epithelium, are particularly susceptible to accumulation of OXPHOS defects over time; however, the effects on the stem cells are unknown. We have crossed a mouse model in which intestinal stem cells are labelled with EGFP (Lgr5‐EGFP‐IRES‐creERT2) with a model of accelerated mtDNA mutagenesis (PolgAmut/mut) to investigate the effect of OXPHOS dysfunction on colonic stem cell proliferation. We show that a reduction in complex I protein levels is associated with an increased rate of stem cell cycle re‐entry. These changes in stem cell homeostasis could have significant implications for age‐associated intestinal pathogenesis. [ABSTRACT FROM AUTHOR]

The pathogenesis of declining bone mineral density, a universal feature of ageing, is not fully understood. Somatic mitochondrial DNA (mtDNA) mutations accumulate with age in human tissues and mounting evidence suggests that they may be integral to the ageing process. To explore the potential effects of mtDNA mutations on bone biology, we compared bone microarchitecture and turnover in an ageing series of wild type mice with that of the PolgAmut/mut mitochondrial DNA 'mutator' mouse. In vivo analyses showed an age-related loss of bone in both groups of mice; however, it was significantly accelerated in the PolgAmut/mut mice. This accelerated rate of bone loss is associated with significantly reduced bone formation rate, reduced osteoblast population densities, increased osteoclast population densities, and mitochondrial respiratory chain deficiency in osteoblasts and osteoclasts in PolgAmut/mut mice compared with wild-type mice. In vitro assays demonstrated severely impaired mineralised matrix formation and increased osteoclast resorption by PolgAmut/mut cells. Finally, application of an exercise intervention to a subset of PolgAmut/mut mice showed no effect on bone mass or mineralised matrix formation in vitro. Our data demonstrate that mitochondrial dysfunction, a universal feature of human ageing, impairs osteogenesis and is associated with accelerated bone loss. [ABSTRACT FROM AUTHOR]

Murine orthotopic cancer models often require surgery, potentially causing pain or distress. However, analgesics are often withheld because they may alter tumour development. Two orthotopically implanted cancers were investigated in mice pre-treated with meloxicam (10 mg/kg), buprenorphine (0.2 mg/kg) or saline (1 ml/kg). Tumours were imaged and welfare was assessed using body weight, behaviour and nociceptive responses. In study 1, BALB/c mice were inoculated with 4T1 mammary carcinoma or saline during surgery or anaesthesia. As pre-treatment with a single buprenorphine dose appeared beneficial to cancer growth consistency, a second cohort of mice additionally received saline or buprenorphine at 12 and 24 h. Surgery resulted in increased mammary tumour growth and lung metastases. These unwanted effects were lessened by buprenorphine pre-treatment, especially when given repeatedly. Mammary tumour-bearing mice became less active and nociceptive thresholds declined over time, indicating some discomfort as tumours grew. In study 2, C57BL/6 mice received B16 melanoma. This non-surgical model was used to determine whether meloxicam or buprenorphine affected cancer seeding of the lungs. While meloxicam reduced B16 lung seeding, buprenorphine did not. Mechanical thresholds decreased as cancer developed in mice bearing melanoma, but the magnitude of this was insufficient to conclude that there were any significant welfare concerns. This study highlights the scientific value in utilising non-surgical models, where possible. When surgery must be performed at the time of tumour inoculation, the effects of this should be controlled with appropriate analgesics to enhance the value and possibly translation of the research. [ABSTRACT FROM AUTHOR]

Introduction: Age-related cumulative mitochondrial mutations can cause mitochondrial dysfunction. The mitochondrial DNA mutator mouse (PolgAmut/mut) is a model of premature ageing and has been previously shown to develop impaired insulin secretion with age. Methods: Immunofluorescence was used to study mitochondrial respiratory chain protein expression (complex I and IV) and the cell composition in islets. Experiments were conducted on pancreas tissue from PolgAmut/mut mice and age-matched wild type (WT) mice at two ages: 12 weeks (young) and 44 weeks (old). Results: (1) Comparing young WT mice versus old WT mice, there was no difference in islet complex I expression, while islet size and beta cell number increased with age (both P<0.01). (2) Comparing young PolgA mut/mut mice versus young WT mice, complex I expression was significantly lower (P<0.01) in islets from young PolgA mut/mut mice. However, there were no significant differences in islet size and cell composition between young PolgA mut/mut and young WT mice. (3) Comparing old PolgA mut/mut mice versus old WT mice, complex I expression was significantly lower (P<0.01) and complex IV expression was significantly higher (P<0.01) in islets from the old PolgA mut/mut mice. Old PolgA mut/mut islets had a lower beta cell percentage (mean ± SEM; 71.8 ± 4 % vs. 89.3 ± 4% P<0.01) but a higher alpha cell percentage (mean ± SEM; 29.6 ± 4 % vs. 12.5 ± 5%; P<0.01) versus old WT mice (both P<0.01). Conclusions: In PolgA mut/mut mice, complex I deficiency was already present in the islets of young mice and persisted with age. This was associated with a proportional increase in alpha cells and decrease in beta cells in islets from old PolgA mut/mut versus the old WT mice. We conclude that complex I deficiency in PolgA mut/mut mice is linked to altered islet cell composition with increasing age. Disclosure: X. Yu: None. C. Arden: None. C. Chen: None. C. Bradshaw: None. J. Whitehall: None. M.G. White: None. S.J. Anderson: None. J.A. Shaw: Advisory Panel; Self; Sanofi. Other Relationship; Self; Novo Nordisk A/S. D. Turnbull: None. L. Greaves: None. M. Walker: None. [ABSTRACT FROM AUTHOR]