TMBIM-2 links neuronal mitochondrial stress to systemic adaptation via calcium signaling

Mitochondria are central hubs of cellular metabolism, calcium (Ca²⁺) homeostasis, and stress adaptation (1). The mitochondrial unfolded protein response (UPR^mt) is a key protective mechanism that maintains mitochondrial function under a variety kind of stresses. While the UPR^mt is extensively studied within individual cells, recent work has revealed its systemic, cell-nonautonomous nature (2, 3). Specifically, mitochondrial stress in neurons can activate the UPR^mt in distal tissues, such as the intestine, influencing whole-organism physiology. However, the precise mechanism on how this inter-tissue communication is achieved remains poorly understood.

A new study by Li et al. (4) investigates this question using Caenorhabditis elegans as a model. Through a genetic screen for regulators of neuron-to-intestine UPR^mt signaling, they identify a transmembrane Bax inhibitor motif-containing (TMBIM)-2 protein (previously known as XBX-6) as an essential regulator of systemic mitochondrial stress response. TMBIM-2, the C. elegans homolog of human TMBIM-2, is highly expressed in neurons and potentially plays a conserved role in Ca²⁺ homeostasis (5). By taking advantage of genetic and imaging approaches, the authors provided compelling evidence showing that neuronal mitochondrial stress induces spatiotemporal dynamics of Ca²⁺ oscillations at the synapses of ADF sensory neurons in a TMBIM-2–dependent manner. Importantly, these oscillations appeared to be essential for the activation of the neuronal-to-intestinal UPR^mt.

In support of a pivotal role of mitochondrial Ca²⁺ buffering capacity in shaping intracellular Ca²⁺ dynamics and orchestrating inter-tissue stress communication, Li et al. unveiled that ADF neuron-specific knockout of mcu-1, which encodes a highly selective and conductive mitochondrial Ca²⁺ uniporter (MCU) (6), is sufficient to trigger TMBIM-2–dependent Ca²⁺ oscillations as well as intestinal UPR^mt activation. Additionally, enhancing mitochondrial Ca²⁺ buffering capacity by overexpressing MCU-1 within neurons attenuated inter-tissue UPR^mt activation.

Further mechanistic studies revealed that TMBIM-2 functions by interacting with MCA-3, an ortholog of mammalian plasma membrane Ca²⁺-ATPase (PMCA) that employs ATP hydrolysis to transport Ca²⁺ from the cytosol to extracellular spaces (7), to regulate Ca²⁺ efflux at the plasma membrane of neuronal synapses. Indeed, loss of mca-3 impairs the Ca²⁺ oscillations and abolishes neuronal-to-intestinal UPR^mt activation. Likewise, pharmacological inhibition of MCA-3 by caloxin 2A1, a specific PMCA inhibitor, attenuates the systemic UPR^mt response, highlighting the importance of precise Ca²⁺ regulation in stress communication.

Importantly, knockout of tmbim-2 significantly suppressed the Ca²⁺-dependent neurotransmitter release from ADF neurons, and supplementation of serotonin effectively restored neuronal-to-intestinal UPR^mt activation in tmbim-2 mutants. These results strongly support a model that TMBIM-2 enhances neuronal-to-intestinal mitochondrial stress communication by facilitating serotonin release of ADF neurons (Fig. 1 A). Given serotonin’s well-characterized role in regulating mood, behavior, and metabolism (8), these findings highlight that mitochondrial stress, when properly regulated, may have beneficial effects on systemic physiology.

Moreover, Li et al. demonstrate that aging is associated with a decline in TMBIM-2 expression, leading to reduced Ca²⁺ oscillations, impaired serotonin release, and diminished UPR^mt activation in peripheral tissues. Overexpression of TMBIM-2 in neurons not only restores these functions but also preserves pathogen-induced aversive learning behavior in aging animals and extends lifespan (Fig. 1 B). These results suggest a model in which age-related decline in TMBIM-2 impairs mitochondrial stress signaling, leading to metabolic dysfunction and cognitive decline. Enhancing TMBIM-2 expression or targeting Ca²⁺ oscillatory mechanisms could thus represent novel therapeutic strategies for age-related disorders.

One potential antiaging therapy could involve enhancing TMBIM-2 function or mimicking its effects to restore Ca²⁺ homeostasis in aging neurons. Meanwhile, pharmacological approaches targeting mitochondrial Ca²⁺ channels, such as MCU inhibitors or PMCA activators, might help mitigate age-related neurodegeneration. Additionally, given the observed decline in TMBIM-2 with age, gene therapy, or small molecules that boost its expression could be explored as neuroprotective strategies.

Beyond its implications for aging and neurodegeneration, this study highlights an underappreciated link between mitochondrial stress and neurotransmission. Neurons rely on mitochondria not only for ATP production but also for buffering intracellular Ca²⁺ levels (9). Disruptions in mitochondrial Ca²⁺ homeostasis can lead to excessive cytosolic Ca²⁺, altering synaptic function and plasticity. By demonstrating that mitochondrial stress induces controlled Ca²⁺ oscillations, Li et al. suggest that neurons actively leverage mitochondrial stress signals to coordinate systemic stress responses. Traditionally, mitochondrial dysfunction is associated with energy deficits and synaptic failure. However, the authors report that prolonged mitochondrial stress enhances neurotransmission via Ca²⁺ oscillations. This counterintuitive mechanism suggests that mild mitochondrial stress may confer adaptive advantages and play an adaptive role in maintaining neuronal function and inter-tissue signaling.

Interestingly, several other studies have also implied that transient mitochondrial stress could enhance synaptic function in mammalian neurons. For example, mild mitochondrial depolarization has been linked to increased neurotransmitter release and synaptic plasticity (10). The findings by Li et al. further support this concept, showing that sustained Ca²⁺ oscillations facilitate serotonin release and systemic UPR^mt activation. This raises the possibility that mitochondrial stress adaptation mechanisms could be harnessed to improve neuronal resilience in aging and disease.

An important question that remains is how TMBIM-2 regulates MCA-3 activity at the molecular level. The interaction between these proteins may involve direct binding, posttranslational modifications, or additional signaling intermediates. Structural studies on TMBIM-2 and MCA-3 could provide additional insights into their functional relationship. Moreover, it will be important to determine whether similar mechanisms also operate in mammalian neurons. Age-related decline in neuronal TMBIM-2 expression has been observed in multiple species, including mice and humans (4). Given that mammalian TMBIM-2 is enriched in the central nervous system and has been implicated in neuroprotection (11), its conserved role in neuronal Ca²⁺ homeostasis and mitochondrial stress response warrants further investigation.

Another avenue for future research is to explore whether other neurotransmitters participate in systemic UPR^mt regulation. While serotonin is a key mediator in C. elegans, mammalian stress responses involve multiple neurochemical pathways (12), including norepinephrine, dopamine, and acetylcholine. Investigating whether these neurotransmitters contribute to mitochondrial stress adaptation in higher organisms could provide broader insights into the neurobiology of aging and metabolic regulation.

In summary, Li et al. uncover a crucial role for TMBIM-2 in coordinating neuronal mitochondrial stress responses through Ca²⁺ oscillations and serotonin signaling. Their findings provide new insights into systemic stress adaptation and aging, with potential implications for neurodegenerative diseases. Given the evolutionary conservation of TMBIM proteins, future studies exploring their role in mammalian models may uncover novel therapeutic targets for metabolic and neurodegenerative diseases.