Treatment and prevention of pathological mitochondrial dysfunction in retinal degeneration and in photoreceptor injury.

Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and age-related chronic diseases, including those of genetic origin. Several of these diseases are rare, typically defined in the United States as an illness affecting fewer than 200,000 people in the U.S. population, or about one in 1600 individuals. Vision impairment due to mitochondrial dysfunction in the eye is a prominent feature evident in numerous primary mitochondrial diseases and is common to the pathophysiology of many of the familiar ophthalmic disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma and retinopathy of prematurity - a collection of syndromes, diseases and disorders with significant unmet medical needs. Focusing on metabolic mitochondrial pathway mechanisms, including the possible roles of cuproptosis and ferroptosis in retinal mitochondrial dysfunction, we shed light on the potential of α-lipoyl-L-carnitine in treating eye diseases. α-Lipoyl-L-carnitine is a bioavailable mitochondria-targeting lipoic acid prodrug that has shown potential in protecting against retinal degeneration and photoreceptor cell loss in ophthalmic indications.

Pathogenic mitochondrial dysfunction and metabolic abnormalities.

Herein we trace links between biochemical pathways, pathogenesis, and metabolic diseases to set the stage for new therapeutic advances. Cellular and acellular microorganisms including bacteria and viruses are primary pathogenic drivers that cause disease. Missing from this statement are subcellular compartments, importantly mitochondria, which can be pathogenic by themselves, also serving as key metabolic disease intermediaries. The breakdown of food molecules provides chemical energy to power cellular processes, with mitochondria as powerhouses and ATP as the principal energy carrying molecule. Most animal cell ATP is produced by mitochondrial synthase; its central role in metabolism has been known for >80 years. Metabolic disorders involving many organ systems are prevalent in all age groups. Progressive pathogenic mitochondrial dysfunction is a hallmark of genetic mitochondrial diseases, the most common phenotypic expression of inherited metabolic disorders. Confluent genetic, metabolic, and mitochondrial axes surface in diabetes, heart failure, neurodegenerative disease, and even in the ongoing coronavirus pandemic.

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs.

In this review we outline a rationale for identifying neuroprotectants aimed at inducing endogenous Klotho activity and expression, which is epigenetic action, by definition. Such an approach should promote remyelination and/or stimulate myelin repair by acting on mitochondrial function, thereby heralding a life-saving path forward for patients suffering from neuroinflammatory diseases. Disorders of myelin in the nervous system damage the transmission of signals, resulting in loss of vision, motion, sensation, and other functions depending on the affected nerves, currently with no effective treatment. Klotho genes and their single-pass transmembrane Klotho proteins are powerful governors of the threads of life and death, true to the origin of their name, Fates, in Greek mythology. Among its many important functions, Klotho is an obligatory co-receptor that binds, activates, and/or potentiates critical fibroblast growth factor activity. Since the discovery of Klotho a little over two decades ago, it has become ever more apparent that when Klotho pathways go awry, oxidative stress and mitochondrial dysfunction take over, and age-related chronic disorders are likely to follow. The physiological consequences can be wide ranging, potentially wreaking havoc on the brain, eye, kidney, muscle, and more. Central nervous system disorders, neurodegenerative in nature, and especially those affecting the myelin sheath, represent worthy targets for advancing therapies that act upon Klotho pathways. Current drugs for these diseases, even therapeutics that are disease modifying rather than treating only the symptoms, leave much room for improvement. It is thus no wonder that this topic has caught the attention of biomedical researchers around the world.

Diagnostic and therapeutic approach to pituitary incidentalomas.

OBJECTIVE: To review data on epidemiology, differential diagnosis, clinical, laboratory, and imaging findings, natural history, and management of incidentally discovered pituitary lesions (pituitary incidentalomas). METHODS: A nonsystematic review was conducted, including articles indexed in Index Medicus that contained reference to incidentally discovered pituitary masses (pituitary incidentalomas). RESULTS: Both autopsy and sensitive neuroimaging studies (including magnetic resonance imaging) suggest that pituitary incidentalomas are common, affecting approximately 10% of the general population. Although typically small (less than 10 mm in greatest diameter) and clinically silent, some pituitary incidentalomas may be hormonally active or cause mass effects by compressing neighboring structures. In addition, a minority of these lesions may grow over time; hence, long-term follow-up is necessary. Therapeutic interventions, including dopamine agonist therapy (in the case of prolactin-secreting adenomas) or transsphenoidal resection, are indicated in the case of pituitary lesions that are hormonally active, cause mass effects, or increase in size. CONCLUSION: Pituitary incidentalomas are common and constitute a heterogeneous group with regard to pathologic features, clinical, laboratory, and imaging characteristics, natural history, and growth potential. Currently available evidence suggests that many hormonally nonfunctioning pituitary incidentalomas causing no mass effects can be safely managed by follow-up surveillance. Nonetheless, more data are needed for further elucidation of the natural history of these lesions and for improvement in accurate and noninvasive diagnosis and in prediction of growth potential of pituitary incidentalomas. Improved understanding of the pathogenesis of this heterogeneous group of lesions may also lead to the development of novel, noninvasive therapeutic agents, rationally designed to interact with well-characterized molecular targets.