Skeletal muscle is a dynamic organ, characterized by an incredible ability to rapidly increase its rate of energy consumption to sustain activity. Muscle mitochondria provide most of the ATP required for contraction via oxidative phosphorylation. Here we found that skeletal muscle mitochondria express a unique MCU complex containing an alternative splice isoform of MICU1, MICU1.1, characterized by the addition of a micro-exon that is sufficient to greatly modify the properties of the MCU. Indeed, MICU1.1 binds Ca one order of magnitude more efficiently than MICU1 and, when heterodimerized with MICU2, activates MCU current at lower Ca concentrations than MICU1-MICU2 heterodimers. In skeletal muscle in vivo, MICU1.1 is required for sustained mitochondrial Ca uptake and ATP production. These results highlight a novel mechanism of the molecular plasticity of the MCU Ca uptake machinery that allows skeletal muscle mitochondria to be highly responsive to sarcoplasmic [Ca] responses.
Background
Considerable attention has been paid to perfluoroalkyl compounds (PFCs) because of their worldwide presence in humans, wildlife, and environment. A wide variety of toxicological effects is well supported in animals, including testicular toxicity and male infertility. For these reasons, the understanding of epidemiological associations and of the molecular mechanisms involved in the endocrine-disrupting properties of PFCs on human reproductive health is a major concern.
Objective
To investigate the relationship between PFC exposure and male reproductive health.
Design
This study was performed within a screening protocol to evaluate male reproductive health in high schools.
Patients
This is a cross-sectional study on 212 exposed males from the Veneto region, one of the four areas worldwide heavily polluted with PFCs, and 171 nonexposed controls.
Main Outcome Measures
Anthropometrics, seminal parameters, and sex hormones were measured in young males from exposed areas compared with age-matched controls. We also performed biochemical studies in established experimental models.
Results
We found that increased levels of PFCs in plasma and seminal fluid positively correlate with circulating testosterone (T) and with a reduction of semen quality, testicular volume, penile length, and anogenital distance. Experimental evidence points toward an antagonistic action of perfluorooctanoic acid on the binding of T to androgen receptor (AR) in a gene reporter assay, a competition assay on an AR-coated surface plasmon resonance chip, and an AR nuclear translocation assay.
Discussion
This study documents that PFCs have a substantial impact on human health as they interfere with hormonal pathways, potentially leading to male infertility.
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