Wang L., Zhou X., Lu T. “Role of mitochondria in physiological activities, diseases, and therapy.” Molecular Biomedicine 6 (42), 19 June 2025 — open-access review
1. What the review sets out to do
Provide a one-stop synthesis of how mitochondria support normal physiology, how their dysfunction drives a broad spectrum of disorders, and what the most promising mitochondria-targeted therapies look like today and in the pipeline. (link.springer.com)
2. Core physiological themes
Theme
Key take-aways
Bioenergetics & signalling
Beyond ATP production, mitochondria act as hubs for Ca²⁺ buffering, ROS signalling, apoptosis, innate immunity and metabolic crosstalk. (link.springer.com)
Dynamics (fission/fusion)
Balanced activity of Drp1, Mfn1/2 and OPA1 keeps the network adaptable; imbalance precipitates fragmentation or hyperfusion with pathological consequences. (link.springer.com)
Quality control (mitophagy)
PINK1–Parkin and receptor-mediated mitophagy selectively cull damaged organelles, integral to neuronal and cardiac resilience. (link.springer.com)
Transport & communication
TRAK/Miro motors, ER-mitochondria contact sites and inter-cellular transfer mechanisms extend mitochondrial influence well beyond their own membranes. (link.springer.com)
MitoQ, SkQ1, elamipretide; several in Phase II/III trials.
Scavenge mtROS without quenching physiological redox signalling. (link.springer.com)
Modulating dynamics & quality control
mdivi-1 (Drp1 inhibitor), urolithin A (mitophagy booster).
Restore fission–fusion balance, enhance clearance of defective mitochondria. (link.springer.com)
Genome editing / gene therapy
mitoTALENs, DdCBE base-editing, AAV-P1ND4v2; early clinical trials.
Correct pathogenic mtDNA or nuclear-encoded mitochondrial genes. (link.springer.com)
Mitochondrial transplantation (MT)
Autologous or MSC-derived organelles tested in cardiac ischemia and myopathies.
Supply healthy mitochondria to energy-starved tissues. (link.springer.com)
The paper’s Table 2 lists ~25 ongoing or completed clinical trials covering these modalities. (link.springer.com)
5. Emerging & future directions highlighted
Ketogenic diet and other metabolic re-programmers to supply alternative fuels and trigger adaptive mitohormesis. (link.springer.com)
Mitochondria-targeted nanomaterials for precision delivery of drugs, photosensitisers or imaging probes. (link.springer.com)
Luminoptogenetics – blue-light–gated channels built into the inner membrane for tumour-selective killing. (link.springer.com)
Enhancing NK-cell mitochondrial fitness to revitalise anti-tumour immunity. (link.springer.com)
6. Key challenges the authors flag
Dual genome complexity – therapies must account for both mtDNA and nuclear control.
Targeted delivery – getting drugs, genes or transplanted mitochondria to the right cells without off-target harm.
Heterogeneity & specificity – mitochondrial phenotypes differ by tissue, disease stage and even cell subtype.
Ethical and regulatory hurdles around heritable mtDNA editing and organelle transplantation. (link.springer.com)
7. Take-home message
Mitochondria sit at the nexus of energy, signalling and cell fate. Their conserved vulnerabilities mean that mitochondria-centric interventions are poised to deliver broad therapeutic pay-offs, but success will require solving delivery, specificity and ethical puzzles first. The review serves as a state-of-the-art roadmap (mid-2025) for researchers and clinicians entering the era of mitochondrial medicine.
What this 2025 review brings to the table that earlier papers did not
Novel element
Why it matters
Where it appears in the paper
One-stop “cross-walk” that links four core mitochondrial processes (fission/fusion, mitophagy, transport, inter-organelle communication) to every major disease class and to therapies that target each process.
Previous reviews usually treated physiology, pathology or therapy in isolation; here the authors map the same mechanistic axes across all three domains, giving researchers a ready-made conceptual framework.
Abstract & Introduction, especially the paragraph that sets out the four processes (link.springer.com)
First side-by-side inventory of ≥70 mitochondria-targeted clinical trials across 14 disease areas (Table 2).
Earlier lists were disease-specific (e.g., just neurodegeneration). By collating oncology, metabolic, cardiovascular, rare mito-disorders and more, the review lets drug developers spot “platform” opportunities and repurposing chances at a glance.
Spotlight on very new therapeutic concepts that have barely entered the literature: • Mitochondria-targeted nanomaterials for drug delivery and imaging • Luminoptogenetic gene therapy (blue-light–gated channelrhodopsin + nanoluciferase in the inner membrane) for tumour-selective killing • Boosting NK-cell mitochondrial fitness to revive anti-tumour immunity
These strategies were reported only in late-2024/2025 primary papers and had not yet filtered into mainstream reviews. Their inclusion signals to readers where the cutting edge is moving next.
“Potential solutions and innovative approaches” section (link.springer.com)
Detailed discussion of mitochondrial transplantation (MT)—bench protocols, early human data, and immunological hurdles.
MT has been mentioned piecemeal since 2018, but this is the first review to synthesise pre-clinical cardiology data with the nascent compassionate-use trials in metabolic myopathies.
Explicit treatment of the “dual-genome problem” and the need for personalised mitochondrial medicine.
The paper argues that successful interventions must reconcile mtDNA and nuclear-encoded factors and proposes genotype-guided dosing—even for antioxidant trials—something earlier reviews largely ignored.
Challenges subsection (discussion of dual-genome complexity, patient variability) (link.springer.com)
In short
While the article is a review, its novelty lies in scope and synthesis: it pulls disparate, very recent strands of mitochondrial biology and therapeutics into a coherent, mechanistic roadmap, backed by the first pan-disease clinical-trial census and an early look at cutting-edge modalities like luminoptogenetics and NK-cell metabolic re-arming. For anyone planning 2025–2027 research or drug-development programmes, it captures where the frontier has just moved.
What the authors set out to do
This is a June 2025 narrative review that asks a simple question with big implications: how exactly does faulty mitochondria drive the vicious circle of metabolic drift, low-grade inflammation and tissue senescence that we recognise as “ageing”? To answer it, the authors:
Recap mitochondrial structure and the canonical functions (ATP, redox, TCA intermediates).
Walk through how mitochondrial stress signalling (mtROS, mtDNA, UPR^mt, cGAS–STING, NLRP3, mitokines) fuels chronic inflammation and the senescence-associated secretory phenotype (SASP).
Highlight the emerging role of mitochondrial metabolites as epigenetic cofactors (α-KG, acetyl-CoA, NAD⁺, fumarate, etc.) that re-write the nuclear programme of ageing cells.
Map these mechanisms onto major age-related diseases (neuro-, cardio-, metabolic, cancer).
Because it is a review rather than primary research, “novelty” is conceptual rather than experimental. The two noteworthy advances are:
Novel contribution
Why it matters
Integrated “metabolite–inflammation–epigenome” loop – the review threads together data showing that TCA-cycle metabolites shuttle to the nucleus, act as chromatin cofactors, and thereby lock cells into a pro-inflammatory, senescent state. Earlier reviews treated these as parallel stories; here they are presented as one feed-forward circuit.
Provides a mechanistic scaffold that links three ageing hallmarks (dysmetabolism, mitochondrial dysfunction, epigenetic drift) into a single targetable axis. (pmc.ncbi.nlm.nih.gov)
Cross-tissue mitochondrial stress signalling – the authors emphasise mitokines and UPR^mt–mediated organ-to-organ communication (e.g., nerve-to-gut PDI-6/Wnt pathway) as an under-explored driver of systemic ageing.
Moves the field from “cell-autonomous” to “organism-level” thinking and justifies multi-tissue intervention designs. (pmc.ncbi.nlm.nih.gov)
Critical appraisal
Strengths
Comprehensiveness – cites >390 papers up to early-2025, pulling in the latest genetics (mtDNA heteroplasmy GWAS), metabolite clocks and senolytic trials.
Mechanistic synthesis – successfully marries metabolic biochemistry with innate-immune signalling and chromatin biology.
Translational awareness – dedicates a full section to clinical-stage approaches (metformin PEN2-AMPK pathway, mitochondrial replacement therapy, NAD⁺ salvage in NK cells).
Limitations & gaps
Issue
Comment
Little critical weighting of evidence
Pathways are listed as if equally proven; contradictory data (e.g., tissue-specific roles of mtROS) are not discussed.
Under-representation of mitochondrial dynamics
Fusion/fission and mitochondria-lysosome contacts get brief mention despite strong links to ageing.
Few human-omics datasets
Gene-expression or metabolomic clock data could have strengthened clinical relevance.
Sex- and tissue-specific nuances overlooked
Ageing trajectories differ by sex and tissue; review treats findings as universal.
Figures could be clearer
The key “loop” and cross-talk concepts appear only in text plus a dense schematic (Fig 2); a modular diagram would aid readers.
Bottom line
The paper will not give you new bench data, but it does give the field an updated conceptual map in which mitochondrial metabolites, inflammatory sensors and epigenetic writers form a self-reinforcing ageing circuit that extends beyond individual cells. That integrative lens—and the call for multi-target, multi-tissue interventions—is its chief contribution.
Comprehensiveness – cites >390 papers up to early-2025, pulling in the latest genetics (mtDNA heteroplasmy GWAS), metabolite clocks and senolytic trials.
Mechanistic synthesis – successfully marries metabolic biochemistry with innate-immune signalling and chromatin biology.
Translational awareness – dedicates a full section to clinical-stage approaches (metformin PEN2-AMPK pathway, mitochondrial replacement therapy, NAD⁺ salvage in NK cells).