Mitochondria are often described as cellular power stations, but in cancer they are also dynamic structures that constantly divide and fuse. This remodeling helps cells respond to changing energy demands, eliminate damaged organelles and distribute mitochondria during cell division. In many tumors, however, the balance shifts toward excessive fission, producing numerous short, fragmented mitochondria. A central regulator of this process is dynamin-related protein 1, or Drp1. When activated, Drp1 moves to the mitochondrial surface and constricts the organelle until it splits. The researchers observed higher levels of activated Drp1, marked by phosphorylation at serine 616, in hepatocellular carcinoma cells than in normal liver-derived cells. The cancer cells also had more of the fission-associated protein Fis1 and less of the fusion proteins mitofusin 2 and OPA1. Under the microscope, their mitochondrial networks were visibly less tubular and more fragmented.

The team focused on what this structural disruption might do to the tricarboxylic acid cycle, a sequence of reactions that converts carbon derived from carbohydrates, fats and proteins into usable metabolic intermediates and reducing equivalents. Particular attention fell on succinate dehydrogenase, or SDH, an unusual enzyme complex with a dual role. Within the tricarboxylic acid cycle, SDH converts succinate into fumarate. At the same time, it forms Complex II of the electron-transport chain, transferring electrons from FADH2 to ubiquinone and linking nutrient metabolism to oxidative phosphorylation. SDH contains four subunits, including SDHB, which helps form the enzyme’s catalytic and electron-transfer machinery. If SDH activity falls, succinate can accumulate instead of being efficiently converted into fumarate. Because succinate can influence gene regulation, inflammation and cellular signaling, its buildup may alter the tumor environment far beyond the mitochondrion.

Evidence from human samples supported this model. The investigators analyzed paired tumor and nearby non-tumorous liver tissue from 150 patients enrolled through the Taiwan Liver Cancer Network. SDHB messenger RNA was lower in tumor tissue, regardless of whether patients had hepatitis B, hepatitis C or neither infection. In a separate analysis using publicly available liver-cancer data, patients whose tumors expressed more SDHB had longer overall survival and relapse-free survival. The researchers also measured succinate in serum from the 150 patients and 47 healthy volunteers. Patients with hepatocellular carcinoma had higher circulating succinate, with a mean concentration of 23.3 micromolar and values ranging from 6.3 to 104.9 micromolar. Higher serum succinate was associated with shorter overall survival, although it was not significantly linked to relapse-free survival. The authors caution that tumor SDHB expression and serum succinate were not directly correlated in the same individual, so the clinical observations are complementary rather than proof of a single causal chain.

Experiments in cultured cells then traced the proposed mechanism. Two liver-cancer cell lines, Huh7 and HepG2, released more succinate into their surrounding medium and had lower SDH activity than THLE-2 cells, a non-cancerous human liver epithelial model. Suppressing SDHB with small interfering RNA increased succinate secretion, enhanced Drp1 activation and raised the number of fragmented mitochondria. The opposite manipulation produced the reverse effect: engineering Huh7 cells to overexpress SDHB increased SDH activity, reduced extracellular succinate, dampened Drp1 activation and restored a more tubular mitochondrial network. Adding succinate back to those SDHB-enhanced cells pushed the mitochondria toward fragmentation again. Together, these results suggest a positive feedback loop: mitochondrial fission suppresses SDH and promotes succinate accumulation, while succinate itself stimulates Drp1-dependent fission.

The researchers tested the feedback mechanism from another direction by neutralizing succinate outside the cell. An antibody directed against succinate reduced mitochondrial fragmentation and increased tubular mitochondrial forms, whereas adding succinate at a concentration of 1 millimolar increased Drp1 activation both in whole-cell extracts and in isolated mitochondrial fractions. The cancer cells also migrated less effectively after Drp1 was silenced or chemically inhibited, suggesting that the pathway affects invasive behavior as well as metabolism. Succinate is already known to function as an “oncometabolite”—a metabolic intermediate that accumulates abnormally and alters cell signaling. Inside cells, excess succinate can inhibit prolyl hydroxylase enzymes, stabilizing the transcription factor HIF-1α and mimicking aspects of low oxygen. Outside cells, it can act through surface receptors and influence neighboring cancer cells, immune cells and blood-vessel formation. The new findings add mitochondrial shape to that network of succinate-driven effects.

To see whether the observations extended beyond cell cultures, the scientists implanted Huh7 cells under the skin of immunodeficient mice. Animals received saline or Mdivi-1, a compound commonly used experimentally to inhibit Drp1-mediated mitochondrial fission, twice each week for three weeks. By the third week, tumors in treated mice were more than 50 percent smaller by volume than those in control animals, and their excised tumors weighed less. Histological analysis also showed a reduced metastatic burden in the lungs. Plasma succinate rose several-fold after tumor implantation in untreated mice but was lower in animals receiving Mdivi-1. Tumors from treated animals contained more SDHB, as well as higher levels of several fusion-associated proteins, and less activated Drp1 and Fis1. The results are consistent with the proposed model in which restoring mitochondrial balance preserves SDH and limits succinate release.

The animal findings nevertheless require careful interpretation before they can be translated into a treatment strategy. Mdivi-1 may affect biological processes beyond Drp1, and lowering plasma succinate could partly reflect the smaller tumors rather than a direct metabolic effect. The xenograft experiment used a small number of mice, outcome assessment was not blinded, and the tumors were implanted subcutaneously rather than arising in a liver with an intact immune system. The researchers also have not established how mitochondrial fragmentation lowers SDHB messenger RNA. Possible explanations include altered transcription through nuclear respiratory factors, accelerated messenger-RNA degradation by microRNAs or retrograde signals generated by mitochondrial stress, such as changes in calcium or MAP kinase activity. Nor has the study proved that extracellular succinate acts through SUCNR1, a known succinate receptor, to phosphorylate Drp1. Those unanswered questions will be important for developing more selective drugs.

Even with those limitations, the study offers a striking view of cancer metabolism as a self-reinforcing circuit rather than a collection of isolated defects. In hepatocellular carcinoma cells, fragmented mitochondria appear to compromise the SDH step of the tricarboxylic acid cycle, allowing succinate to accumulate and escape into the tumor surroundings. That succinate then feeds back onto the cells, activating Drp1 and driving further mitochondrial fragmentation. Interrupting the circuit genetically or with a pharmacological tool restored SDH activity, reduced succinate and suppressed cancer-cell migration; in mice, the intervention also reduced tumor growth and metastasis. Future work will need to test whether the same mechanism operates across genetically diverse liver tumors, whether succinate measurements can improve existing prognostic tools and whether safer, more specific inhibitors can target mitochondrial fission without disrupting healthy tissues. For now, the work identifies a potentially exploitable metabolic vulnerability—and a molecule already circulating in the blood—that may help reveal when liver cancer has entered a more aggressive state.

Kaposi’s sarcoma-associated herpesvirus, also known as human herpesvirus 8, is well recognized for its association with malignancies, including Kaposi’s sarcoma and certain lymphomas, primarily in immunocompromised patients. While its oncogenic facets have been intensively studied, the intricate mechanisms by which KSHV modulates cellular environments to facilitate its lifecycle remain incompletely understood. This new study focuses on an often-overlooked aspect of viral strategy: the manipulation of mitochondrial dynamics to circumvent immune surveillance and favor productive infection.

Central to this viral manipulation is a protein encoded by KSHV homologous to the cellular Bcl-2 family, denoted as viral Bcl-2 (vBcl-2). Unlike its cellular counterparts, which primarily regulate apoptosis, this viral incarnation assumes a more multifaceted role. Zhu et al. demonstrate that vBcl-2 effectively reprograms mitochondrial morphology, favoring fission over fusion—a state characterized by fragmented, punctate mitochondria. The researchers elucidate a direct molecular interaction underpinning this morphological shift, spotlighting the host nucleoside diphosphate kinase NM23-H2 as a critical partner in this process.

NM23-H2 is classically known for its enzymatic activity in nucleotide metabolism, catalyzing the transfer of γ-phosphates among nucleoside diphosphates and triphosphates. In this context, however, it assumes a novel role as a facilitator of mitochondrial fission through its partnership with vBcl-2. The viral protein binds NM23-H2, which subsequently stimulates GTP loading on dynamin-related protein 1 (DRP1), a GTPase crucial for mitochondrial fission. This biochemical activation prompts DRP1 to oligomerize on the mitochondrial outer membrane, driving the mechanical processes that fragment the organelle.

This mitochondrial fragmentation is no incidental side effect. Rather, it strategically dampens host antiviral signaling by disrupting the function of mitochondria-anchored antiviral proteins. One key player is the mitochondrial antiviral signaling protein MAVS, which typically forms aggregates on the outer membrane upon detection of viral RNA. These aggregates serve as platforms to activate downstream signaling cascades culminating in interferon production, a cornerstone of the host’s innate immunity. By inducing mitochondrial fission, KSHV effectively inhibits MAVS aggregation, thereby silencing the interferon response and undermining a crucial antiviral defense.

The authors contrasted the wild-type vBcl-2 with a mutant variant defective in binding NM23-H2, discovering striking differences in functional outcomes. Cells expressing the mutant failed to undergo mitochondrial fission, which correlated with a resurgence of MAVS aggregation and vigorous interferon signaling. This immune activation, in turn, rendered virion assembly defective, underscoring the importance of vBcl-2-mediated mitochondrial reconfiguration in viral progeny production. Thus, the virus’s capacity to trigger mitochondrial fission is directly linked to both immune evasion and successful virion morphogenesis.

Delving deeper into the host response, Zhu et al. identified two interferon-stimulated genes that act as antiviral effectors restricting vBcl-2-dependent virion assembly. While the study does not elaborate extensively on these genes’ identities, their emergence highlights the layered nature of host restriction mechanisms that continue to exert pressure on viral replication even when key pathways like MAVS signaling are subdued. This finding also suggests that therapeutic strategies could aim to bolster or mimic these intrinsic antiviral factors.

The translational potential of these insights was explored through a high-throughput small molecule screening aimed at identifying inhibitors that disrupt the interaction between vBcl-2 and NM23-H2. Among the candidates, the authors discovered a compound capable of selectively obstructing this viral-host protein interface, leading to marked suppression of virion production in vitro. This pharmacological blockade reactivates mitochondrial antiviral signaling by preserving MAVS aggregation, reinstating interferon responses, and curbing virus proliferation.

This study provides a vivid example of how viruses exploit mitochondrial dynamics not only to create a favorable niche for replication but also to actively subvert host immunity. The identification of the vBcl-2 and NM23-H2 interaction as a pivotal node in this manipulation opens new avenues for antiviral drug development which, by targeting host-virus protein interactions, may offer durable therapeutic benefits with reduced likelihood of resistance.

Moreover, these findings compel a broader reevaluation of mitochondrial fission’s role in viral pathogenesis. Traditionally viewed as cellular responses to stress or damage, mitochondrial morphological changes are increasingly recognized as deliberate viral strategies to silence immune barriers. The KSHV case study advances our understanding by revealing a mechanism through which a viral Bcl-2 analog usurps host enzymatic machinery to modulate mitochondrial shape, thus intersecting with innate immunity at a fundamental level.

The implications extend beyond KSHV itself, as many viruses encode Bcl-2 homologs or manipulate mitochondrial dynamics to varying degrees. Understanding how these strategies converge on common host pathways such as DRP1 activation and MAVS suppression offers a framework for investigating immune evasion among diverse viral families. Therapeutic strategies emerging from this paradigm have the potential for broad-spectrum application against pathogens that exploit analogous mitochondrial interfaces.

From a cell biology perspective, this work also enriches the discourse on mitochondrial dynamics by linking it directly to antiviral signaling fidelity. It underscores that mitochondrial morphology is not a simple passive indicator of cellular health but an active modulator of immune signal transduction. This functional duality presents a conceptual leap—considering organelle ultrastructure as a dynamic immunoregulatory element shaped by viral manipulation.

While the study predominantly used in vitro models, the findings invite future in vivo investigations to assess how modulating mitochondrial dynamics affects KSHV pathogenesis and immune responses within an organismal context. Understanding the temporal kinetics of viral-induced mitochondrial fragmentation, its reversibility, and interactions with other host pathways will be critical to translating these molecular insights into tangible clinical interventions.

Collectively, Zhu et al. unveil an elegant viral strategy whereby KSHV encodes a Bcl-2 homolog that commandeers a host nucleotide kinase to activate DRP1-driven mitochondrial fission. This reconfiguration impedes MAVS aggregation, silences interferon responses, and facilitates virion assembly, securing viral propagation. The therapeutic disruption of the vBcl-2–NM23-H2 interaction thereby emerges as a promising avenue to reinstate host immunity and inhibit viral production. This study not only deepens our understanding of mitochondrial dynamics in immunological defense but also highlights a novel antiviral target at the virus-mitochondria interface.

The multidimensional nature of these findings accentuates the sophistication with which viruses exploit host cell biology and reveals mitochondria as a nexus of pathogenic control. It challenges researchers and clinicians alike to consider the organelle as a frontline in the immunological war against infection, ripe for targeted therapeutic intervention.

Subject of Research: Viral manipulation of mitochondrial dynamics to evade host immunity and promote Kaposi’s sarcoma-associated herpesvirus (KSHV) production.

Article Title: Kaposi’s sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production.

Article References:
Zhu, Q., McElroy, R., Machhar, J.S. et al. Kaposi’s sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production. Nat Microbiol (2025). https://doi.org/10.1038/s41564-025-02018-3

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