Mitochondrial OPA1 deficiency causes reversible defects in adult neurogenesis-associated spatial memory in mice

Abstract

Mitochondria are integrative hubs central to cellular adaptive pathways. Such pathways are critical in highly differentiated post-mitotic neurons, the plasticity of which sustains brain function. Consequently, defects in mitochondrial dynamics and quality control appear instrumental in neurodegenerative diseases and may also participate in cognitive impairments. To directly test this hypothesis, we analyzed cognitive performances in a mouse mitochondria-based disease model, due to haploinsufficiency in the mitochondrial optic-atrophy-type-1 (OPA1) protein. While in Dominant Optic Atrophy (DOA) models, the known main symptoms are late onset visual deficits, we discovered early impairments in hippocampus-dependent spatial memory attributable to defects in adult neurogenesis. Moreover, less connected hippocampal adult-born neurons showed a decrease in mitochondrial content. Remarkably, modulating mitochondrial function through voluntary exercise or pharmacological treatment restored spatial memory.Altogether, our study identifies a crucial role for OPA1-dependent mitochondrial functions in adult neurogenesis, and thus in hippocampal-dependent cognitive functions. More generally, our findings show that adult neurogenesis is highly sensitive to mild mitochondrial defects, generating impairments in spatial memory that can be detected at an early stage and counterbalanced by physical exercise and pharmacological targeting of mitochondrial dynamics. Thus, early amplification of mitochondrial function appears beneficial for late-onset neurodegenerative diseases.

Hippocampal mitophagy contributes to spatial memory via maintaining neurogenesis during the development of mice

“…Previous research has demonstrated that such biological changes enhanced cognitive functions like spatial memory in animals with various pathological conditions. 21,23,40 However, it remains unclear whether the upregulation of neurogenesis under normal physiological conditions affects hippocampus-related cognitive functions in adult mice. Our behavioral results demonstrated that UMI-77 increased the duration of spatial memory in adult mice.…”

“…Mitochondrial dynamics, constituting essential mechanisms by which the organism safeguards mitochondrial function, serve as crucial regulatory factors in adult neurogenesis under pathological conditions. [20][21][22][23][24] However, their role as a modulator of neurogenesis during developmental processes remains unclear. Our results indicate that there is a decline in mitophagy from adolescence to adulthood, along with a simultaneous decrease in mitochondrial fusion.…”

“…To investigate why spatial memory differs between adolescent and adult mice, we focused on hippocampal neurogenesis, a key factor in spatial memory. 21,23,27 We used 5-bromodeoxyuridinc (BrdU) to tag the cells added to the DG within 24 h, and doublecortin (DCX) served as a marker for young neurons aged between 3 days and 3 weeks. Our results, shown in Figure 3A-C, indicate that adult mice had significantly fewer newborn neurons than adolescent mice.…”

“…17,18 In animal models of aging 19 and various diseases, impaired mitochondrial function plays a crucial role in the decline in neurogenesis. This is evident in conditions such as AD, 20 dominant optic atrophy, 21 and PD. 22 Mitochondrial dynamics, including fusion, fission, and mitophagy, are essential for maintaining overall mitochondrial health, thus playing a significant role in the regulation of neurogenesis.…”

“…22 Mitochondrial dynamics, including fusion, fission, and mitophagy, are essential for maintaining overall mitochondrial health, thus playing a significant role in the regulation of neurogenesis. For example, in mice with a heterozygous knockout of the mitochondrial fusion protein Opa-1, a dysfunction in hippocampal neurogenesis occurs, leading to impaired spatial memory 21 ; ganglioside GD3 regulates adult hippocampal neurogenesis through the turnover modulation of the mitochondrial fission protein Drp1 23 ; and mice with a knockout of the ubiquitin-dependent mitophagy protein PTEN-induced kinase 1 (PINK1) exhibit abnormalities in hippocampal metabolism and neurogenesis. 24 The exact effect of mitochondrial dynamics on changes in neurogenesis throughout the transition from adolescence to adulthood is not yet fully understood.…”