Cancer and neurodegeneration meet
Status and Bioenergetics Liaison in Cancer and Neurodegeneration all oxidations that meet the conditions of specificity and reversibility. of the Research Topic. Non-coding RNAs: Crossing the Aisle from Cancer to Neurodegeneration Cancer and neurodegeneration meet. EMBO Mol. Med. EMBO Mol Med. Jul;2(7) doi: /emmm Cancer and neurodegeneration meet. de Strooper B. PMCID: PMC
A common challenge in the next future will be the identification and the use of more physiological stimuli to induce mitochondrial damage, and mitophagy, to better mimic the in vivo mechanism of pathophysiology of neurodegenerative diseases.
A mouse model of DJ-1 knockout presents mitochondrial fragmentation [ ], increased ROS production, and reduced respiration rates accompanied by basal autophagy impairment [ ]. Complex I dysfunctions are common in PD, and its inhibition, by rotenone or 6-hydroxydopamine 6-OHDA treatment, results in a DRP1-dependent mitochondrial fragmentation in neurons , so suggesting another link between bioenergetic dysfunctions and altered mitochondrial dynamics in neurodegenerative diseases.
Abnormal aggregation of mitochondria is common in the subsarcolemmal region of muscles and in the anterior horn neurons of the lumbar spinal cord [ 8889 ]. At ultrastructural levels, in the case of ALS, mitochondria show disorganized cristae with expansion of intermembrane space IMS [ 9091 ]. Moreover, motor neurons from mice overexpressing SOD1-G93A show impaired mitochondrial fusion both in axons and in the cell body with impaired retrograde axonal transport and reduction of frequency and speed of the movement [ 93 ].
Contrary effects regarding oxidative phosphorylation impairment related to this disease have been published. On the other hand, in other studies, no energetic impairment was observed in lymphoblasts and muscle cells from ADOA patients [ 9697 ]. Whatever the case, consistent with the role of OPA1 in regulating mitochondrial dynamics, mitochondrial fragmentation is a common feature of ADOA with a severity score of the pathology directly proportional to the level of fragmentation observed [ 9798].
Interestingly, fibroblasts from ADOA patients also reveal a major sensitivity to death stimuli [ 98 ], in line with the antiapoptotic role of OPA1 described above [ 8 ]. Recently, a possible link with mitochondrial dynamics has been presented in a genome-wide linkage scan study, in which a mutation in Parl the mitochondrial protease responsible for OPA1 cleavage, [ ] has been associated with LHON [ ].
Moreover, ganglioside-induced differentiation-associated protein 1 GDAP1whose mutations cause an autosomal recessive form of CMT, appears to be related to mitochondrial fission in mammalian cells [ ]. In addition, in a mouse model of apoptosis-inducing factor AIF deficiency, MFN1 levels are decreased in the cerebellum and are accompanied by death of Purkinije cells [ ]. This phenomenon is generally observed in many neurological diseases such as autism, HD, AD, multiple system atrophy, and epilepsy [ ].
Consistently, also in Mfn2 knock-out systems, death of Purkinije cells has been observed, confirming a role for MFNs in protecting against lack of mtDNA and dysfunction of mitochondria in the cerebellum [ ].
In the last decade, a link between neurological and lymphatic aspects has emerged in schizophrenia [ ]. Recently, a study in schizophrenia-derived lymphoblastoids revealed altered oxidative phosphorylation at level of complex I and clustering of mitochondria in a limited area of the cell, with a reduction in OPA1 expression levels [ ]. To conclude, neurons rely on mitochondrial distribution, function, and dynamics to allow synapses and dendrites formation, energy supply, and quality control.
The main properties of neurons constitute risk factors themselves if we consider the effects of mitochondrial dysfunctions. First, they are cells highly demanded in energy; second, they have long processes connecting the soma to synapses and dendritic spines; third, they are long-lived postmitotic cells. Neuroinflammatory and Autoimmune Diseases Little is known about the link between mitochondrial dynamics and neuroinflammatory or autoimmune diseases.
In this section we present correlations described to date with multiple sclerosis MS and type I diabetes, as examples for this category of diseases see Table 3. We then introduce some general outcomes about mitochondrial dynamics and T-cell compartment with the potential for opening up new perspectives regarding cellular mechanisms and clinical therapies for many pathologies.
Mitochondrial dynamics and neuroinflammatory and autoimmune diseases. Optic Neuritis and Multiple Sclerosis Optic neuritis ON is a neuropathy characterized by demyelination of the optic nerve; it can be present by itself or as part of MS. Multiple sclerosis is an autoimmune disorder characterized by chronic demyelination of the central nervous system CNS.
The pathogenesis of MS is thought to involve self-antigen-reactive T lymphocytes that have the capacity to invade the CNS and to promote tissue damage. It is not rare to find mtDNA mutations and mitochondrial abnormalities in patients affected by ON [ ].
This mutation leads to reduction of respiratory rates with lower ATP production [ ], which is implicated in demyelination of axons in MS [ ]. Interestingly, it has been shown that symptoms of autoimmune disorders, including MS, improve during pregnancy due, at least in part, to the expression of embryo-derived preimplantation factor PIF.
This protein is able to reduce neuroinflammation and to promote neural repair in the experimental autoimmune encephalomyelitis EAE model of MS, through a general decrease in proinflammatory cytokine and chemokine secretion, and a downregulation of proapoptotic factors and of activating and migrating proteins such as OPA1 [ ].
Coronary endothelial cells from diabetic mice are characterized by fragmented mitochondria with a downregulation of OPA1 and an upregulation of DRP1 [ ].
Interestingly, phb-genetic ablation results in aberrant mitochondrial cristae structure and an increased apoptosis, dependent on increased proteolytic processing of OPA1 [ 15 ].
Moreover, it has been shown that the embryo-derived preimplantation factor PIF also prevents type I diabetes in mouse models of this disease [ ].
Mitochondrial Morphology and T-Cell Function The importance of mitochondrial localization and activity in T cell function is well established. Mitochondria usually fragment and relocalize at the immunological synapse in close proximity to the plasma membrane to buffer entrance and to avoid calcium-dependent T-cell inactivation [ ].
Moreover, upon activation, T cells migrate to the site of inflammation towards a chemoattractant gradient. Our group reported that mitochondria allow lymphocyte migration by relocating and accumulating at the uropod the posterior area of an activated T cell where they can provide the necessary energy to class II myosin proteins, these being the major cellular motors.
Interestingly, this reorganization needs mitochondrial fission while a forced fusion inhibits both mitochondrial relocalization and lymphocyte migration [ 45 ].
In recent years, the polarization of mitochondria towards cell-cell surface has also been shown to occur between natural killer NK and tumoral cells . GAL-1 sensitizes resting and activated T cells to FAS-mediated cell death program, which is characterized by mitochondrial dysfunctions, membrane potential alteration, mitochondrial fission, and cytochrome release [ ].
It still remains to be elucidated whether or not mitochondrial dynamics play a crucial role in other important physiological processes in T cells. Finally, CD47 can trigger cell death in a B lymphocyte leukemia. Also this apoptotic pathway is characterized by DRP1 translocation to mitochondria, which depends on chymotrypsin-like proteases, loss and ROS production [ ].
This last observation is an indication of a possible role of mitochondrial dynamics in general in the whole immune system, more than only in the T-cell physiology and pathophysiology.
In particular, the residual content of cycasin in cycad flour was very strongly correlated with the risk for both ALS and P-D among Chamorros Kisby et al. Methylazoxymethanol is a potent alkylating agent that spontaneously breaks down into reactive molecules, notably methyldiazonium ions and carbon-centered free radicals that methylate nucleic acids at the O6- N7- and C8 positions of guanine Matsumoto and Higa, ; Shank and Magee, ; Nagata and Matsumoto, ; Nagasawa et al.
It appears that varying amounts of DNA damage lead to the activation of unique as well as common sets of miRNAs, suggesting that the nature and intensity of DNA damage are key factors. Although several DNA damage-responsive targets have been identified, many remain to be discovered, including those activated in the brain by environmental agents that induce DNA damage.
Rodents that have been chronically treated with the MAM precursor azoxymethane AOM are widely used as models for investigating the pathogenesis and chemoprevention of human colon carcinoma Rosenberg et al.
A remarkable number of miRNAs exhibits differential expression in colon cancer tissues; these miRNAs alter cell proliferation, apoptosis, and metastasis through their interactions with intracellular signaling networks Schetter and Harris, ; Wu et al.
For example let-7, miRa and miR are strongly linked to KRAS knockdown and activation of the epidermal growth factor receptor-mitogen activated protein kinase EGFR-MAPK pathway, whereas miR and miR are associated with augmentation or inactivation of the phosphatidylinositolkinase pathway Aslam et al. Activation of these downstream pathways results in autonomous tumor cell growth, increased cell survival, and initiation of angiogenesis.
Epidermal growth factor receptors EGFR suppress the tumor suppressors miR and miR, which coordinately control multiple targets of downstream cell-signaling pathways i. Systems Biology of MAM in Brain Developmental neurotoxicity of MAM MicroRNAs play an important role in normal development of the brain, where they dictate neuronal cell identity, neurite growth, synaptic development, and neuronal plasticity Wheeler et al.
Deficiency of Dicer is associated with progressive loss of miRNAs, followed by cerebellar degeneration and development of ataxia Schaefer et al. Dicer also appears to be a target of several environmental mutagens resulting in the interference of miRNA maturation Ligorio et al.
Redox Status and Bioenergetics Liaison in Cancer and Neurodegeneration
The latter studies suggest that environmental agents that damage DNA might indirectly alter brain development by perturbing the maturation of miRNAs. Although the involvement of miRNAs has yet to be defined, the cerebellum is reproducibly perturbed when MAM or its glucoside cycasin is administered to rodents. MAM kills or arrests neuroblasts undergoing mitosis.
Rodents treated with MAM acetate in utero or within days of birth show strikingly abnormal development of the cerebellum associated with partial destruction of the external granular layer Hirono and Shibuya, ; Shimada and Langman, ; Jones and Gardner, ; Lovell and Jones, Apoptotic cells in the external granular cell layer appear 24 h after MAM treatment, peak at 48 h and decrease at 72 h Gobe, ; Lafarga et al. Rats exposed in utero [gestational day 15 GD15 or less] to MAM or MAM acetate show microcephaly, and some develop endocrine adenomas, oligodendromas, and schwannomas, or tumors at peripheral sites Lacqueur and Spatz, Exposure at later stages of embryonic brain development i.
Calcium-signaling, glutamate receptor signaling, and long-term potentiation were the predominant cell-signaling pathways perturbed in the hippocampus of rats treated on GD17 with MAM Lodge and Grace, ; Hradetzky et al. Glutamate receptor signaling and RNA post-transcriptional modification, molecular transport and RNA trafficking, were also among the top molecular networks perturbed in the prefrontal cortex of rats exposed on GD17 to MAM Merker et al.
In wild-type mice, MAM reduced the density of neurons in the granule cell layer and disrupted the organization of the Purkinje cell layer. MAML, low magnification 3.
Arrows indicate disorganization of Purkinje cell layer and stars denote reduced density of neurons in granule cell layer. The pronounced effect of MAM on both fetal and neonatal glutamatergic neurotransmission and neural development, which are altered in schizophrenia Kantrowitz and Javitt,suggests the developing brain is especially sensitive to DNA damage. Since the processing of mRNA and the chromatin remodeling machinery were also key targets of MAM in the fetal and neonatal brain, these studies suggest that MAM alters the development of neurons by a mechanism involving both DNA damage and epigenetic mechanisms.
We tested the hypothesis that the DNA-damaging properties of MAM, which are mutagenic and tumorigenic in cycling cells of the colon epithelium Rosenberg et al. Two separate laboratories treated groups of mice with a single systemic dose of MAM, and the combined data were mined for common brain transcriptional profiles. A third laboratory conducted blinded analyses of brain O6-methylguanosine levels. Signaling pathways associated with cancer and human neurodegenerative disease were activated in the mature mouse brain as the result of unrepaired MAM-induced DNA damage Kisby et al.
A computational approach was used to determine which miRNAs are likely to regulate MAM-modulated gene expression in the adult mouse brain. Each of these gene hubs was computationally analyzed to identify potential regulating miRNAs. These data demonstrate that multiple miRNAs likely regulate the MAM-generated hubs, a finding that has been shown by others Nohata et al.
MiR has an important role in the brain, where it is essential for activity-dependent dendritic outgrowth, nerve growth cone guidance, and size of dendritic spines of hippocampal neurons Schratt et al.Cells At Work- Cancer Cell [Intro]
Silencing of miR expression reduces dendritic spine density and renders mice refractory to seizures and hippocampal injury caused by status epilepticus Jimenez-Mateos et al. MiR is also a powerful inducer of pluripotent stem cell differentiation and functions as a regulator of cell proliferation, apoptosis, and migration during lung development Zhang et al. The expression of miR is reduced in gastrointestinal stromal tumors Haller et al.
MiR is proposed to play critical roles in the development and progression of malignant peripheral nerve sheath tumors Gong et al. Downregulation of miR activates Ras in gastric cancer cells Lam et al. Transfection of miR into human trabecular meshwork cells increased levels of apoptosis, decreased viability, and increased the accumulation of oxidized proteins, decreased induction of endoplasmic reticulum stress response markers, and reduced expression of inflammatory mediators Li et al.
MiR has a binding site for angiopoietin-1, which is a vascular strengthening factor during vascular development and a protective factor for pathological vascular inflammation and leakage, including brain vascular leakage as occurs in stroke Chen et al. MiR expression promotes colorectal cancer growth by down-regulating expression of the CHD5 tumor suppressor Cai et al.
Increased miR expression is linked with progression and vascular invasion of oral carcinoma Chang et al. MiR is also implicated as a tumor suppressor for melanoma invasion Levy et al. MiR acts as a tumor suppressor by inhibiting proliferation and inducing apoptosis of human breast cancer cells Yamamoto et al. What is molecular medicine? My view is that it is the scientific discipline that applies the tool-box of molecular biology to understand the pathogenesis of disease.
International Journal of Cell Biology
Ideally such work translates into novel diagnostics and novel drug targets and treatments. It is clear that molecular medicine is not only borrowing knowledge and tools from other life sciences, but the field is itself also driving the development of novel technologies and the creation of new insights in biology.
In fact, the nature of molecular medicine research, oriented towards pathophysiological processes, systems and models makes this field one of the spearheads of the rapid evolution in life sciences. Molecular genetics is exemplary in that regard; the massive investments made to sequence and annotate the human genome and to refine the analysis of genetic information were only possible because of the idea that medical benefits will emerge down the line.
Obviously all life sciences profit from this boost. It was enriching to see how Cancer and Neurodegeneration researchers focusing on abnormal cell growth and cell loss, respectively, share so many questions, knowledge and tools… Research into areas such as cancer, cardiovascular disease or neurology affects other disciplines and propels our knowledge with increasing velocity.
EMBO Molecular Medicine aims to divulge this knowledge and promote a faster pace for its translation into the clinics. As our understanding of human pathophysiology increases so does our realization of the inevitable cross-talk between different molecular and cellular processes.