Tackling dysfunction of mitochondrial bioenergetics in the brain

Oxidative phosphorylation (OxPhos) is the basic function of mitochondria, although the landscape of mitochondrial functions is continuously growing to include more aspects of cellular homeostasis. Thanks to the application of -omics technologies to the study of the OxPhos system, novel features emerge from the cataloging of novel proteins as mitochondrial thus adding details to the mitochondrial proteome and defining novel metabolic cellular interrelations, especially in the human brain. We focussed on the diversity of bioenergetics demand and different aspects of mitochondrial structure, functions, and dysfunction in the brain. Definition such as ‘mitoexome’, ‘mitoproteome’ and ‘mitointeractome’ have entered the field of ‘mitochondrial medicine’. In this context, we reviewed several genetic defects that hamper the last step of aerobic metabolism, mostly involving the nervous tissue as one of the most prominent energy-dependent tissues and, as consequence, as a primary target of mitochondrial dysfunction. The dual genetic origin of the OxPhos complexes is one of the reasons for the complexity of the genotype-phenotype correlation when facing human diseases associated with mitochondrial defects. Such complexity clinically manifests with extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. Finally, we briefly discuss the future directions of the multi-omics study of human brain disorders

RCC1L (WBSCR16) isoforms coordinate mitochondrial ribosome assembly through their interaction with GTPases

Mitochondrial translation defects can be due to mutations affecting mitochondrial-or nuclear-encoded components. The number of known nuclear genes involved in mitochondrial translation has significantly increased in the past years. RCC1L (WBSCR16), a putative GDP/GTP exchange factor, has recently been described to interact with the mitochondrial large ribosomal subunit. In humans, three different RCC1L isoforms have been identified that originate from alternative splicing but share the same N-Terminus, RCC1LV1, RCC1LV2 and RCC1LV3. All three isoforms were exclusively localized to mitochondria, interacted with its inner membrane and could associate with homopolymeric oligos to different extent. Mitochondrial immunoprecipitation experiments showed that RCC1LV1 and RCC1LV3 associated with the mitochondrial large and small ribosomal subunit, respectively, while no significant association was observed for RCC1LV2. Overexpression and silencing of RCC1LV1 or RCC1LV3 led to mitoribosome biogenesis defects that resulted in decreased translation. Indeed, significant changes in steady-state levels and distribution on isokinetic sucrose gradients were detected not only for mitoribosome proteins but also for GTPases, (GTPBP10, ERAL1 and C4orf14), and pseudouridylation proteins, (TRUB2, RPUSD3 and RPUSD4). All in all, our data suggest that RCC1L is essential for mitochondrial function and that the coordination of at least two isoforms is essential for proper ribosomal assembly

Multimode photonic molecules for advanced force sensing

We propose a force sensor, with optical detection, based on a reconfigurable multicavity photonic molecule distributed over two parallel photonic crystal membranes. The system spectral behaviour is described with an analytical model based on coupled mode theory and validated by finite difference time domain simulations. The deformation of the upper photonic crystal membrane, due to a localized vertical force, is monitored by the relative spectral positions of the photonic molecule resonances. The proposed system can act both as force sensor, with pico-newton sensitivity, able to identify the position where the force is applied, and as torque sensor able to measure the torsion of the membrane along two perpendicular directions

Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction

Background: Charcot-Marie-Tooth disease (CMT) type 4B3 (CMT4B3) is a rare form of genetic neuropathy associated with variants in the MTMR5/SBF1 gene. MTMR5/SBF1 is a pseudophosphatase predicted to regulate endo-lysosomal trafficking in tandem with other MTMRs. Although almost ubiquitously expressed, pathogenic variants primarily impact on the peripheral nervous system, corroborating the involvement of MTMR5/SBF1 and its molecular partners in Schwann cells-mediated myelinization. Case presentation: We report a case of severe CMT4B3 characterized by early-onset motor and axonal polyneuropathy in an Italian child in absence of any evidence of brain and spine MRI abnormalities or intellectual disability and with a biochemical profile suggestive of mitochondrial disease. Using an integrated approach combining both NGS gene panels and WES analysis, we identified two novel compound heterozygous missense variants in MTMR5/SBF1 gene, p.R763H (c.2291G > A) and p.G1064E (c.3194G > A). Studies in muscle identified partial defects of oxidative metabolism. Conclusion: We describe the first case of an early onset severe polyneuropathy with motor and axonal involvement, due to recessive variants in the MTMR5/SBF1 gene, with no evidence of brain and spine MRI abnormalities, intellectual disability, no clinical and neurophysiological evidences of distal sensory impairment, and rapid neuromuscular deterioration. This report suggests that MTMR5/SBF1 should be considered in cases of infantile-onset CMT with secondary mitochondrial dysfunction

The Impact of the COVID-19 pandemic on outdoor physical activities for people with disabilities, including the risks for psychophysical well-being

The restrictions and social distancing measures due to the COVID-19 pandemic have created many obstacles in the practice of outdoor physical activity (OPA) throughout the world, particularly for the most vulnerable people, such as those with disabilities. The aim of this study was to explore the impact of pandemic-related limitations on the OPA of an Italian cohort of people with disabilities practicing sports. A retrospective observational study was conducted using an online survey. The questionnaire was distributed to 121 disabled athletes who practiced different outdoor physical activities. A total of 96 completed the survey, which collected demographic data, information about daily outdoor physical activity and sports habits, and about physical and psychological health before and during the pandemic. The frequency of daily OPA per week, along with the hours of physical activity, significantly decreased during the pandemic compared to those of the year before (p < 0.0001). A statistically significant deterioration was also found in the physical and mental well-being of disabled athletes during the pandemic (p < 0.0001) when compared to those from the year before the advent of COVID-19. This research demonstrated the negative impact of COVID-19 restrictions on OPA levels and on the physical and mental well-being of athletes with disabilities. It also highlighted a new challenge regarding the sustainability and integration of the national health system, demonstrating the necessity of improving the consistent accessibility of people with disabilities to OPA, both under normal conditions and emergency situations, in order to guarantee their psychophysical well-being

Respiratory chain complex I, a main regulatory target of the cAMP/PKA pathway is defective in different human diseases

In mammals, complex I (NADH-ubiquinone oxidoreductase) of the mitochondrial respiratory chain has 31 supernumerary subunits in addition to the 14 conserved from prokaryotes to humans. Multiplicity of structural protein components, as well as of biogenesis factors, makes complex I a sensible pace-maker of mitochondrial respiration. The work reviewed here shows that the cAMP/PKA pathway regulates the biogenesis, assembly and catalytic activity of complex I and mitochondrial oxygen superoxide production. The structural, functional and regulatory complexity of complex I, renders it particularly vulnerable to genetic and sporadic pathological factors. Complex I dysfunction has, indeed, been found, to be associated with several human diseases. Knowledge of the pathogenetic mechanisms of these diseases can help to develop new therapeutic strategies. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved

Integrated nano-opto-electro-mechanical sensor for spectrometry and nanometrology

Spectrometry is widely used for the characterization of materials, tissues, and gases, and the need for size and cost scaling is driving the development of mini and microspectrometers. While nanophotonic devices provide narrowband filtering that can be used for spectrometry, their practical application has been hampered by the difficulty of integrating tuning and read-out structures. Here, a nano-opto-electro-mechanical system is presented where the three functionalities of transduction, actuation, and detection are integrated, resulting in a high-resolution spectrometer with a micrometer-scale footprint. The system consists of an electromechanically tunable double-membrane photonic crystal cavity with an integrated quantum dot photodiode. Using this structure, we demonstrate a resonance modulation spectroscopy technique that provides subpicometer wavelength resolution. We show its application in the measurement of narrow gas absorption lines and in the interrogation of fiber Bragg gratings. We also explore its operation as displacement-to-photocurrent transducer, demonstrating optomechanical displacement sensing with integrated photocurrent read-out

Near-field investigation of luminescent hyperuniform disordered materials

Disordered photonic nanostructures have attracted tremendous interest in the past three decades, not only due to the fascinating and complex physics of light transport in random media, but also for peculiar functionalities in a wealth of interesting applications. Recently, the interest in dielectric disordered systems has received new inputs by exploiting the role of long-range correlation within scatterer configurations. Hyperuniform photonic materials, that share features of photonic crystals and random systems, constitute the archetype of systems where light transport can be tailored from diffusive transport to a regime dominated by light localization due to the presence of photonic band gap. Here, advantage is taken of the combination of the hyperuniform disordered (HuD) design in slab photonics, the use of embedded quantum dots for feeding the HuD resonances, and near-field hyperspectral imaging with sub-wavelength resolution in the optical range to explore the transition from localization to diffusive transport. It is shown, theoretically and experimentally, that photonic HuD systems support resonances ranging from strongly localized modes to extended modes. It is demonstrated that Anderson-like modes with high Q/V are created, with small footprint, intrinsically reproducible and resilient to fabrication-induced disorder, paving the way for a novel photonic platform for quantum applications

Nanoscale mechanical actuation and near-field read-out of photonic crystal molecules

We employed the contact forces induced by a near-field tip to tune and probe the optical resonances of a mechanically compliant photonic crystal molecule. Here, the pressure induced by the near-field tip is exploited to control the spectral proprieties of the coupled cavities in an ultrawide spectral range, demonstrating a reversible mode shift of 37.5 nm. Besides, by monitoring the coupling strength variation due to the vertical nanodeformation of the dielectric structure, distinct tip sample interaction regimes have been unambiguously reconstructed with a nano-Newton sensitivity. These results demonstrate an optical method for mapping mechanical forces at the nanoscale with a lateral spatial resolution below 100 nm