Mesenchymal Stem Cells Shift Mitochondrial Dynamics and Enhance Oxidative Phosphorylation in Recipient Cells

Mesenchymal stem cells (MSCs) are the most commonly used cells in tissue engineering and regenerative medicine. MSCs can promote host tissue repair through several different mechanisms including donor cell engraftment, release of cell signaling factors, and the transfer of healthy organelles to the host. In the present study, we examine the specific impacts of MSCs on mitochondrial morphology and function in host tissues. Employing in vitro cell culture of inherited mitochondrial disease and an in vivo animal experimental model of low-grade inflammation (high fat feeding), we show human-derived MSCs to alter mitochondrial function. MSC co-culture with skin fibroblasts from mitochondrial disease patients rescued aberrant mitochondrial morphology from a fission state to a more fused appearance indicating an effect of MSC co-culture on host cell mitochondrial network formation. In vivo experiments confirmed mitochondrial abundance and mitochondrial oxygen consumption rates were elevated in host tissues following MSC treatment. Furthermore, microarray profiling identified 226 genes with differential expression in the liver of animals treated with MSC, with cellular signaling, and actin cytoskeleton regulation as key upregulated processes. Collectively, our data indicate that MSC therapy rescues impaired mitochondrial morphology, enhances host metabolic capacity, and induces widespread host gene shifting. These results highlight the potential of MSCs to modulate mitochondria in both inherited and pathological disease states

Qur’anic Ethics for Environmental Responsibility: Implications for Business Practice

Despite the growing interest in examining the role of religious beliefs as a guide towards environmental conscious actions, there is still a lack of research informed by an analysis of divine messages. This deficiency includes the extent to which ethics for environmental responsibility are promoted within textual divine messages; types of environmental themes promoted within the text of divine messages; and implications of such religious environmental ethics for business practice. The present study attempts to fill this gap by conducting a thorough content analysis of environmental themes within the divine message of Muslims (the Qur’an) focusing on their related ethical aspects and business implications. The analysis has revealed 675 verses in 84 chapters throughout all 30 parts of the Qur’an, with environmental content relating to the core components of the natural world, i.e. human beings, water, air, land, plants, animals, and other natural resources. This environmental content and its related ethics are grounded on the belief that humans are vicegerents of God on the earth and their behaviours and actions are motivated by earthly and heavenly rewards. Implications of these findings for different sectors/businesses are also highlighted

On the Regulation of Mitochondrial Fusion, Fission and Mitochondrial DNA

Mitochondria are functionally and structurally fascinating organelles, well known for their role as the cellular powerhouse. Unlike other membrane bound organelles, mitochondria maintain their own genome (mtDNA), which is present in hundreds of copies per cell, packaged into nucleo-protein structures known as nucleoids. An important regulator of mitochondrial function is their dynamic nature, whereby ongoing fusion and fission events remodel mitochondrial network morphology and influence mitochondrial activity. Dynamic fusion and fission forces are also key for distributing mtDNA nucleoids throughout mitochondrial networks and the maintenance of mtDNA copy number. Notably, mutations in core mitochondrial fusion (MFN2, OPA1) and fission (DRP1) proteins lead to enlarged nucleoids, mtDNA depletion and cause severe mitochondrial diseases. However, we do not completely understand how or why these processes are important for mtDNA. Additionally, there remains a lot to be learned about the molecular regulators mediating fusion and fission of mitochondrial networks. This project set out to characterize novel mitochondrial fusion and fission factors and further understand how defective fusion and fission regulation influence mtDNA dynamics. The work outlined in this thesis showcases three nuclear-encoded mitochondrial disease genes (FBXL4, MSTO1 & MYH14) implicated as regulators of mitochondrial morphology and shown to be important for mtDNA regulation. Firstly, this work characterizes an established mtDNA depletion syndrome gene, FBXL4 and provides the first evidence that FBXL4 protein is a mitochondrial fusion regulator. Secondly, MSTO1, a recently described cytosolic fusion regulator, is highlighted as perturbations in MSTO1 pro-fusion activity gives rise to mtDNA depletion and altered nucleoid distribution. Lastly, the largely uncharacterized non-muscle myosin protein, NMIIC, encoded by MYH14, is highlighted as novel component of the mitochondrial fission machinery. A pathogenic mutation in MYH14 causing peripheral neuropathy reduces fission and adversely affects the distribution of mtDNA nucleoids, particularly at the cell periphery. Through genetic and pharmacological rescue approaches to restore mitochondrial network morphology in these models, this work contributes to our understanding on the interplay between fusion and fission dynamics and mtDNA maintenance

Aberrant Mitochondrial Morphology and Function in the BTBR Mouse Model of Autism Is Improved by Two Weeks of Ketogenic Diet.

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder that exhibits a common set of behavioral and cognitive impairments. Although the etiology of ASD remains unclear, mitochondrial dysfunction has recently emerged as a possible causative factor underlying ASD. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that augments mitochondrial function, and has been shown to reduce autistic behaviors in both humans and in rodent models of ASD. The aim of the current study was to examine mitochondrial bioenergetics in the BTBR mouse model of ASD and to determine whether the KD improves mitochondrial function. We also investigated changes in mitochondrial morphology, which can directly influence mitochondrial function. We found that BTBR mice had altered mitochondrial function and exhibited smaller more fragmented mitochondria compared to C57BL/6J controls, and that supplementation with the KD improved both mitochondrial function and morphology. We also identified activating phosphorylation of two fission proteins, pDRP1S616 and pMFFS146, in BTBR mice, consistent with the increased mitochondrial fragmentation that we observed. Intriguingly, we found that the KD decreased pDRP1S616 levels in BTBR mice, likely contributing to the restoration of mitochondrial morphology. Overall, these data suggest that impaired mitochondrial bioenergetics and mitochondrial fragmentation may contribute to the etiology of ASD and that these alterations can be reversed with KD treatment

Aberrant Mitochondrial Morphology and Function in the BTBR Mouse Model of Autism Is Improved by Two Weeks of Ketogenic Diet.

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder that exhibits a common set of behavioral and cognitive impairments. Although the etiology of ASD remains unclear, mitochondrial dysfunction has recently emerged as a possible causative factor underlying ASD. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that augments mitochondrial function, and has been shown to reduce autistic behaviors in both humans and in rodent models of ASD. The aim of the current study was to examine mitochondrial bioenergetics in the BTBR mouse model of ASD and to determine whether the KD improves mitochondrial function. We also investigated changes in mitochondrial morphology, which can directly influence mitochondrial function. We found that BTBR mice had altered mitochondrial function and exhibited smaller more fragmented mitochondria compared to C57BL/6J controls, and that supplementation with the KD improved both mitochondrial function and morphology. We also identified activating phosphorylation of two fission proteins, pDRP1S616 and pMFFS146, in BTBR mice, consistent with the increased mitochondrial fragmentation that we observed. Intriguingly, we found that the KD decreased pDRP1S616 levels in BTBR mice, likely contributing to the restoration of mitochondrial morphology. Overall, these data suggest that impaired mitochondrial bioenergetics and mitochondrial fragmentation may contribute to the etiology of ASD and that these alterations can be reversed with KD treatment