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Mitochondrial fatty acid synthesis is a little-known but essential pathway that supports energy production and metabolic health.

Summary: Dr. Sara Nowinski explains how mitochondria not only burn fuels to make ATP but also synthesize their own fatty acids inside the matrix; this conserved pathway produces lipoic acid (an essential enzyme cofactor) and longer-chain fats required for proper assembly of the electron transport chain, and disrupting it impairs respiration, glucose handling, and insulin sensitivity while enhancing it appears protective against obesity and heart injury.

About the guest: Sara Nowinski, PhD is an assistant professor in the Department of Metabolism and Nutritional Programming at Van Andel Institute in Grand Rapids, Michigan, where since 2021 she has led a lab focused on mitochondrial biology and the mitochondrial fatty acid synthesis (mitoFAS) pathway.

Topics Discussed:

• Basic mitochondrial energy production: food → pyruvate/fatty acids → acetyl-CoA → TCA cycle → electron transport chain → ATP
• Mitochondrial fatty acid synthesis (mitoFAS): a bacterial-like pathway that builds fats on an acyl carrier protein inside the matrix
• Lipoic acid: an 8-carbon fatty acid made only by mitoFAS, covalently attached to key enzymes (e.g., pyruvate dehydrogenase); cannot be rescued by supplements for cofactor use
• Longer mitoFAS products (14–16 carbons) stabilize electron transport chain assembly factors, explaining why pathway loss collapses respiration even when lipoic acid is intact
• Knocking out mitoFAS causes embryonic lethality, insulin resistance, poor glucose homeostasis, and a rare neurodegenerative disorder (MEPAN syndrome)
• Overexpressing the mitochondrial acyl carrier protein protects mice from diet-induced obesity, insulin resistance, and cardiac injury
• Muscle cell differentiation fails without mitoFAS, hinting at a role in tissue development and repair

Practical Takeaways:

• Supplemental lipoic acid can act as an antioxidant but cannot replace the lipoic acid your mitochondria must make themselves for enzyme function.
• Severe impairment of mitochondrial fatty acid synthesis is linked to insulin resistance and metabolic disruption, suggesting mitochondrial health (beyond just biogenesis) matters for glucose control.

*Not medical advice.

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How internal states like hunger and hormones shape instinctive behaviors, particularly parental care

Episode Summary: Dr. Johannes Kohl explains instinctive behaviors in mammals, emphasizing how states like hunger and hormonal cycles modulate actions such as parental care; they discuss hypothalamic circuits, hormone integration, and pregnancy-induced brain changes, highlighting the balance between motivations like feeding and nurturing offspring.

About the guest: Jonny Kohl, PhD heads the State-Dependent Neural Processing Lab at the Francis Crick Institute in London.

Discussion Points:

• Instinctive behaviors: Pre-wired actions like escaping predators or parental care enable survival without learning, yet remain modifiable by experience and internal states.
• Internal states: Defined as slowly changing conditions (minutes to weeks) like hunger or hormonal fluctuations that influence brain processing & behavior prioritization.
• Hunger regulation: Hypothalamic AGRP neurons detect caloric deficits, creating motivational discomfort relieved by food anticipation, operating on multiple timescales via neurotransmitters & peptides.
• Parental care: Virgin mice show variable pup-directed behaviors; hunger increases aggression, modulated by estrous cycle hormone ratios (estradiol/progesterone).
• Hormone-brain interactions: Steroid hormones like estradiol and progesterone diffuse into the brain, altering gene expression, neuronal excitability, and circuit plasticity over short and long timescales.
• Pregnancy adaptations: Late pregnancy rewires MPOA circuits via surging hormones, preparing robust maternal behavior before birth (anticipatory brain plasticity).

Practical Takeaways:

• Recognize hunger’s impact: Mild food deprivation can heighten irritability or aggression, which can affect social interactions.
• Consider hormonal influences: Cyclical hormone changes affect mood and motivation; tracking cycles may help predict and manage behavioral shifts.
• Prioritize self-care in parenting: Sleep and nutrition deficits mimic hunger states, potentially reducing patience; ensure rest and meals to support nurturing behaviors.
• Question chronic hormone use: Long-term interventions like birth control or testosterone can alter brain function; weigh benefits against potential side effects.

*Not medical adv

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How mitochondria travel between cells and how this hidden communication shapes metabolism, immunity, and even potential therapies.

Episode Summary: Dr. Jon Brestoff talks about mitochondrial dynamics inside cells, their transfer between unrelated cells (distinct from inheritance during division), and its roles in adipose tissue communication, macrophage cleanup, and systemic metabolic signaling; they explore how high-fat diets disrupt this process, potential hormetic benefits, therapeutic mitochondria transplantation for diseases like Leigh syndrome and obesity, and broader immunometabolism crosstalk.

About the guest: Jon Brestoff, MD, PhD is an associate professor of pathology and immunology at Washington University School of Medicine in St. Louis, where he directs the Initiative for Immunometabolism.

Discussion Points:

• Mitochondria per cell range from ~100-5000; they move via fusion/fission, vertical inheritance (cell division), or horizontal transfer without division.
• Transfer mechanisms: free release, extracellular vesicles, or tunneling nanotubes using cytoskeleton transport.
• In healthy fat tissue, adipocytes routinely donate mitochondria to macrophages for degradation (quality control); high-fat (lard-based, long-chain FA) diets block macrophage uptake, diverting mitochondria to other organs.
• Diverted mitochondria may induce “mito-hormesis” (mild oxidative stress boosting antioxidants) or signal adipocyte metabolic status inter-organ.
• Mitochondria transplantation shows promise in animal models for ischemia-reperfusion, obesity, and mitochondrial diseases.
• Immune cells prefer glycolysis but have low mitochondrial biomass; transplanted mitochondria tilt T-cells toward anti-inflammatory regulatory phenotype.
• Circulating cell-free mitochondria rival immune cell numbers.
• Obesity inflammation stems from dying oversized adipocytes releasing lipids/mitochondria, forming crown-like structures with pro-inflammatory macrophages.
• Leigh syndrome from genetic mutations disrupting the electron transport chain.
• Transfer may be an evolutionary relic of endosymbiosis; cells may selectively use exogenous mitochondria like a “generator” during metabolic crisis.

Reference Paper:

• Study: The power and potential of mitochondria transfer

Related Episode:

• M&M 260: Energy Resistance Principle in Life, Healing & Disease | Martin Picard & Nirosha Murugan

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A biophysical rethink of life, health, and disease through the lens of the Energy Resistance Principle (ERP).

Episode Summary: A reframe of biology as energy flow through resistance rather than mere molecular machinery, introducing the Energy Resistance Principle (ERP): life requires a Goldilocks balance of electron flow from food to oxygen via mitochondria; too much or too little resistance drives aging, disease, and death. Explain mitochondria as energy transformers, link ERP to insulin resistance, psychiatric disorders, and healing, and explore health as a dynamic field-like state optimized by flux modulation.

About the guest: Nirosha Murugan, PhD is a biophysicist studying how physical signals pattern biology to decode and reprogram health; Martin Picard, PhD is a mitochondrial psychobiologist at Columbia University, exploring how mitochondrial energy dynamics connect to human experiences, health, and healing. They collaborate on biophotons, light emission, and multi-scale energy signaling.

Discussion Points:

• Mitochondria transform electrons from food into versatile electricity via proton gradients.
• Energy Resistance Principle: transformation needs resistance; chronic high resistance causes dissipative heat, damage, aging.
• GDF15 cytokine signals mitochondrial stress to brain, triggering energy conservation/mobilization.
• Insulin resistance: adaptive defense against electron overload, reversible by fasting/exercise.
• Psychiatric illness: excess brain energy resistance; exercise, keto, psychedelics redistribute flux.
• Health: dynamic optimization of energy resistance, not absence of disease.
• Healing: daily recovery from micro-damage via balanced resistance.
• Future: energy-based diagnostics/therapies (light, TMS) over molecule-only drugs.

*Not medical advice.

Reference Paper: The energy resistance principle

Related Episode:

• M&M 70: Mitochondria, Aging, Cellular Energy, Metabolism, Gray Hair Reversal & Brain-Body Communication | Martin Picard

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How artificial light impacts female menstrual cycles and their relationship to lunar cycles of the moon.

Summary: Dr. Förster talks about how biological clocks, including circadian, tidal, lunar, and annual cycles, regulate behaviors in various species, with a focus on lunar cycle effects on human menstrual cycles. They explore historical and modern data suggesting that menstrual cycles may synchronize with lunar phases, a phenomenon potentially disrupted by modern artificial lighting, particularly blue light from LEDs post-2010. The conversation also covers circadian rhythm mechanisms in fruit flies and humans, highlighting the role of light and neuropeptides in maintaining biological synchrony.

About guest: Charlotte Förster, PhD is a senior professor at the University of Würzburg specializing in chronobiology, particularly circadian rhythms in fruit flies, and has recently explored lunar cycle influences on human menstrual cycles.

Discussion Points:

• Biological Clocks: Various clocks (circadian, tidal, lunar, annual) regulate behaviors; circadian clocks manage 24-hour cycles, while lunar clocks influence reproduction in marine species like corals and Christmas Island crabs.
• Lunar Cycle & Menstruation: Historical data (pre-2010) showed many women’s menstrual cycles synchronized with lunar phases (full or new moon), but this decreased post-2010, possibly due to blue light from LEDs disrupting biological rhythms.
• Blue Light Impact: Blue light from modern devices mimics daylight, potentially desynchronizing circadian and lunar clocks, with melanopsin in the eyes playing a key role in light sensitivity.
• Winter Synchronization: Menstrual cycle synchrony with lunar phases is stronger in winter, particularly January, possibly due to brighter moonlight or gravitational effects when Earth is closest to the Sun.
• Circadian Mechanisms: In fruit flies, 240 neurons manage circadian rhythms via clock genes with a 24-hour feedback loop, conserved in humans, where neuropeptides regulate slower, sustained rhythms.
• Health Implications: Disrupted circadian rhythms can desynchronize body clocks, impacting digestion, immunity, and increasing risks of cardiovascular issues, obesity, and cancer.
• Lifestyle Tips: To maintain synchrony, maximize daytime light exposure, minimize nighttime blue light, time meals appropriately, and exercise during the day, not late at night.

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The genetic & developmental changes behind bipedalism & human anatomy.

Wide release date: October 15, 2025.

Episode Summary: Dr. Terence Capellini talks about the evolution of bipedalism in humans, exploring when and why it emerged, the anatomical changes required, and the genetic mechanisms behind these adaptations. They discuss how environmental shifts, like shrinking forests, drove the need for upright walking, the gradual skeletal changes in the pelvis and limbs, and how these changes may have facilitated larger brain sizes. Capellini highlights the complexity of evolutionary processes, emphasizing the role of multiple genetic changes in regulatory regions rather than single genes.

About the guest: Terence Capellini, PhD is a professor and chair of the Department of Human Evolutionary Biology at Harvard University. His research focuses on developmental genetics and human evolution.

Discussion Points:

• Bipedalism likely became common ~3.5 million years ago with Australopithecus afarensis, with earlier hominins like Ardipithecus showing mosaic traits.
• Environmental changes, such as shrinking forests and expanding grasslands, created selective pressures favoring bipedal locomotion.
• The human pelvis evolved to be shorter, wider, and curved, with muscles like the gluteus medius shifting to stabilize upright walking.
• Genetic changes in non-coding regulatory regions, not protein-coding genes, drive the developmental shifts in pelvic growth, with hundreds of small-effect changes involved.
• Bipedalism may have widened the birth canal, potentially enabling the evolution of larger brains in later hominins like Homo erectus.
• Humans have more slow-twitch muscle fibers than chimpanzees, supporting endurance activities like long-distance running, possibly linked to energetic trade-offs with brain growth.
• Shoulder and arm adaptations for throwing and tool use evolved more gradually, becoming prominent ~2 million years ago with Homo erectus.

Reference paper:

• Study: The evolution of hominin bipedalism in two steps

Related content:

• M&M 171: Comparative Brain Evolution: Mammals, Primates & Humans | Robert Barton

*Not medical advice.

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The biological roots of sleep are tied to mitochondrial metabolism.

Episode Summary: Dr. Gero Miesenböck discusses the evolutionary and metabolic basis of sleep, exploring how mitochondrial energy production in neurons, particularly in fruit flies, drives the need for sleep to manage harmful byproducts like reactive oxygen species and lipid peroxides. They discuss how sleep-inducing neurons sense these byproducts, the role of mitochondrial dynamics, and the broader implications for why all animals, from jellyfish to humans, require sleep. The conversation also touches on how body size and metabolism influence sleep needs across species.

About the guest: Gero Miesenböck, MD is a professor of physiology at the University of Oxford, renowned for his pioneering work in optogenetics and his research on the neurobiology of sleep using fruit flies and mice.

Discussion Points:

• Sleep is universal across animals, even in jellyfish without centralized brains, suggesting a fundamental metabolic purpose tied to mitochondrial energy production.
• Mitochondria produce energy efficiently using oxygen but generate reactive oxygen species that can damage cells through lipid peroxidation, necessitating sleep to repair this damage.
• Sleep-inducing neurons in fruit flies contain sensors that track lipid peroxidation products, acting like a digital memory to signal when sleep is needed.
• Smaller animals with faster metabolisms, like mice, require more sleep and have shorter lifespans due to higher oxygen consumption and oxidative stress.
• Mitochondrial diseases in humans often cause intense tiredness, likely due to increased electron leaks in the mitochondrial energy production process.
• The evolutionary origin of sleep likely stems from the oxygen revolution 2.5 billion years ago, enabling complex life but requiring mechanisms like sleep to manage metabolic side effects.
• Caloric restriction reduces sleep need by lowering the production of harmful metabolic byproducts, supporting the link between metabolism and sleep.

Reference paper:

• Study: Mitochondrial origins of the pressure to sleep

Related content:

• M&M 12: Organisms, Cities, Companies & the Science of Scale | Geoffrey West

*Not medical advice.

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The surprising link between oral bacteria and heart disease.

Episode Summary: Dr. Pekka Karhunen explains the connection between oral bacteria, cholesterol, and cardiovascular disease, discussing how oxidized LDL cholesterol triggers inflammation in arteries, how bacteria from the mouth can infiltrate arterial plaques to form biofilms, and the implications for heart disease prevention through lifestyle changes like better oral hygiene.

About the guest: Pekka Karhunen, MD, PhD is a medical doctor and forensic pathologist with decades of experience, specializing in cardiovascular diseases. He has created a unique biobank of coronary arteries from over 10,000 autopsies conducted in Finland. His research focuses on the role of bacteria in atherosclerosis, particularly through studying coronary artery plaques.

Discussion Points:

• Cholesterol is essential for life, but oxidized low-density lipoprotein (LDL) cholesterol is seen as a foreign substance by the immune system, leading to chronic inflammation in coronary arteries.
• Macrophages ingest oxidized LDL, turning into dysfunctional foam cells that contribute to plaque buildup, known as atheromas, in arteries.
• Plaque rupture, potentially caused by increased pressure from cholesterol accumulation or hemorrhage within the plaque, can trigger heart attacks.
• Bacteria, especially from the mouth, can enter arterial plaques via bacteremia (e.g., from dental procedures) and form biofilms, evading immune detection.
• Biofilms in plaques, made of extracellular matrix like polysaccharides, protect bacteria and may contribute to plaque instability or calcification over time.
• Poor oral hygiene is linked to higher cardiovascular disease risk, as bacteria from dental infections can enter plaques, suggesting dental care as a preventive measure.
• Karhunen’s research found oral bacteria, like Viridans streptococci, in coronary plaques, with unpublished data also detecting gut and skin bacteria, indicating diverse bacterial involvement.

Related content:

• M&M 247: Cholesterol: Immune Benefits, Heart Health, Statins & Research Malpractice | Uffe Ravnskov

*Not medical advice.

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